Reproductive Sciences

Treatment Outcomes and Resistance Patterns in Low Risk GTN: A 270-Patient Experience from a Tertiary Center

Because of the lack of fully successful treatment of low-risk gestational trophoblastic neoplasia (GTN) patients after first-line single-agent chemotherapy, some studies have suggested that these patients should be treated with multi-drug chemotherapy from the outset. A score of 0-4 represents the majority of low risk GTN that has been less studied. The present study aimed to investigate the risk factors associated with resistance to first-line single-agent chemotherapy. This retrospective cohort includes patients diagnosed with low-risk GTN who were treated with single-agent chemotherapy using methotrexate and actinomycin. Factors associated with resistance to first-line chemotherapy were analyzed separately in two groups: those with a score of 0-6 and those with a score of 0-4. A total of 270 patients were studied, all of whom achieved remission. Of these, 75.9% responded to first-line single-agent chemotherapy. Patients aged 40 or older had about 7 times higher odds of treatment resistance than younger patients. Choriocarcinoma increased the odds by 5.5 times, and each 1 cm increase in tumor size raised the odds by 53%. In patients with WHO scores of 0-4, each additional year of age increased resistance odds by 6%, and choriocarcinoma raised it by 7.5 times. In both groups, lung metastasis increased the chance of resistance threefold. Increased age, larger tumor size, increase βhCG level and start of treatment with MTX, increase the likelihood of resistance to first-line chemotherapy in the 0-6 score and in the subgroup with a 0-4 score. Future prospective studies are necessary to validate new models Until then, clinicians should be aware of the limitations of the current system and consider individualized clinical judgment.

Targeting mTOR by CZ415 Suppresses Cell Proliferation and Promotes Apoptosis via Lipin-1 in Cervical Cancer In Vitro and In Vivo

CZ415, a novel inhibitor of mammalian target of rapamycin (mTOR) kinase, has demonstrated anti-tumor activity in several types of cancer. However, its biological function and underlying mechanism of action in cervical cancer (CC) have not been fully studied. Two CC cell lines (Hela and Siha) were treated with increasing concentrations of CZ415. Cell viability was tested with the CCK-8 assay, cell proliferation was determined by Edu staining and the colony formation assay, and apoptosis was determined by flow cytometry and Hoechst 33342 staining. Protein expression was evaluated by western blotting. A nude mouse xenograft model was used to confirm the anti-tumor activity of CZ415 in vivo. Hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining were performed on samples of tumor tissue. Results showed that CZ415 inhibited CC cell survival in a dose- and time-dependent manner, and 100 nanomolar and 48 h were the optimal conditions. In vitro and in vivo experiments showed that treatment with CZ415 significantly inhibited spheroid formation, cell proliferation, and tumor growth. Further studies showed that the anti-cancer effects of CZ415 were due to an induction of apoptosis, which was accompanied by an upregulation of Bax and downregulation of Bcl-2 through Lipin-1. CZ415 also reduced the levels of mTOR/STAT3 expression. However, these phenotypic changes were reversed by overexpression of Lipin-1. Our results suggest that the novel mTOR inhibitor CZ415 mediates tumor malignancy via Lipin-1 and might be useful for treating CC.

Inhibition of Lnc-OC1 Induced Cell Apoptosis and Decreased Cell Viability by Releasing miR-34a and Inhibiting PD-L1 in Endometrial Carcinoma

Now, there is a growing awareness of the role to long non-coding RNAs (lncRNAs) in tumorigenesis and progression of a variety of malignancies including endometrial carcinoma (EC). Here, we explored the potential molecular mechanism of Lnc-OC1, a novel lncRNA, in the development of EC. Our results suggested that Lnc-OC1 was significantly upregulated in EC tissues comparing with normal tissues. Besides, Lnc-OC1 was higher expressed in the more advanced stage of EC. Therefore, Lnc-OC1 might be a crucial regulator in the progress of EC. Moreover, knockdown of Lnc-OC1 leaded to an inhibition of cell viability and a raise of cell apoptosis. In addition, Lnc-OC1 could sponge miR-34a and thus decrease its expression. miR-34a was proved to be a tumor suppressor in different malignance, hence downregulating Lnc-OC1 helped to alleviate EC by releasing miR-34a. Furthermore, rescue experiments significantly indicated that knockdown of Lnc-OC1 inhibited cell growth through repressing PD-L1 expression at least partially. Concisely, our results proved that Lnc-OC1/miR-34a/PD-L1 axis might serve as a therapeutic target of EC.

SPOCK2 Affects the Biological Behavior of Endometrial Cancer Cells by Regulation of MT1-MMP and MMP2

Abnormal expression of SPARC (osteonectin), cwcv and kazal-like domains proteoglycan 2 (SPOCK2) plays a significant role in the development and progression of various human cancers, yet a relationship between SPOCK2 and endometrial cancer (EC) has not been reported. Here, we assessed the potential role and mechanism by which SPOCK2 acts in the pathogenesis and progression of EC. First, protein expression of SPOCK2 in EC tissue from patients was detected by immunohistochemistry and associated clinical data were analyzed. Then, HEC-1A and Ishikawa cells were transfected with an adenoviral vector containing an SPOCK2 recombinant fragment and the biological behavior of transfected cells was observed. Finally, the expression of membrane type 1 matrix metalloproteinase (MT1-MMP) and MMP2 in the transfected cells was detected by Western blot and zymography gel assay to analyze the effect of SPOCK2 on the regulation of the MT1-MMP/MMP2 pathway. We found that there was significantly less SPOCK2 protein expression in the EC tissue than in the normal endometrium tissue, and lack of SPOCK2 protein expression in EC tissue was associated with distant metastasis and myometrial invasion. Upregulation of SPOCK2 in HEC-1A and Ishikawa cells inhibited cell proliferation, invasion, adhesion, and apoptosis. Upregulation of SPOCK2 inhibited the expression of MT1-MMP and MMP2 and activation of MMP2 in HEC-1A and Ishikawa cells. Collectively, our data indicated that SPOCK2 contributed to the progression of EC by regulating the biological behavior of cancer cells, which is achieved partly through regulating protein expression of MT1-MMP and MMP2 and activation of MMP2.

Identification of a Gene Panel for Endometrioid Endometrial Cancer: a Possible Prognostic Value?

The incidence of endometrial cancer (EC) is increasing in developed countries. The most frequent is the endometrioid subtype with usually good prognosis; nevertheless, some cases escape this paradigm and may have recurrence. A recent study from The Cancer Genome Atlas suggested to implement the EC analysis by molecular profile for improving diagnosis, prognosis, and therapeutic treatment. The present preliminary study was performed on 15 G3 endometrioid endometrial cancers (G3 EEC) for the identification of somatic mutations in a panel of specific exons in selected genes as ARID1A, CTNNB1, KRAS, PIK3CA, POLE, PTEN, and TP53. The combined procedure, based on the Sanger sequencing and PCR-high-resolution melting analysis, allowed the identification of variations of the selected gene panel in most of patients (93%) of our cohort. The overall evaluation of mutational load exhibited that the most frequent mutated genes were PTEN (93%), followed by PIK3CA (47%) suggesting a deep involvement of PI3K pathway alteration in G3 EEC. Mutations in TP53 (27%), ARID1A (27%), POLE (13%), and at the lower level in KRAS and CTNNB1 (7%) were also observed (exclusively in FIGO III stage patients). The evaluation of the mutations of our proposed panel (ARID1A, CTNNB1, KRAS, PIK3CA, POLE, PTEN, TP53) is suitable to improve the characterization of G3 EEC and could suggest targetable pathways for development of personalized treatments.

Preoperative Circulating Lymphocyte and Monocyte Counts Correlate with Patient Outcomes in Type I and Type II Endometrial Cancer

Tumor-associated macrophages and tumor-infiltrating lymphocytes are associated with survival in solid malignancies. Given the physiological link to peripheral immune cell counts, we evaluated if peripheral immune cell counts were predictors of outcomes in endometrial cancer. A retrospective study was completed for endometrial cancer cases between 2000 and 2010. Kaplan-Meier, bivariate, and multivariable Cox proportion hazard analyses were performed examining the relations between survival and peripheral immune cell counts. Three hundred ten patients were identified. In bivariate analyses, high monocyte counts (> 0.7 × 10

Endometriosis and Ovarian Cancer: Insights from NHANES and Mendelian Randomization Analysis

Abstract Endometriosis describes the growth of extra-uterine endometrium, causing pain and inflammation, and the condition has been estimated to affect 10% of women of reproductive age. It remains under-diagnosed and has been linked to increased cancer risk. This study evaluated the correlation between endometriosis and cancer. The significance of specific loci to cancer was analyzed via Mendelian randomization (MR). Of the 4092 samples included, cancer diagnoses were self-reported by 326 women with endometriosis and 3766 women without endometriosis. Correlations between individual cancer types and endometriosis were analyzed by multivariable logistic regression models and odds ratios (OR) adjusted for confounders. Mortality was evaluated by Kaplan–Meier survival analysis. Genetic variants associated with endometriosis were linked to ovarian cancer by MR analysis. Women with endometriosis had a higher association of overall cancer (OR = 1.80, 95% CI: 1.19—2.72) and this was especially the case for ovarian cancer (OR = 11.40, 95% CI: 3.00—43.34). Subgroup and sensitivity analyses confirmed the robustness of these results. Kaplan–Meier analysis indicated lower survival from all causes in women with endometriosis (p = 0.022) but no significant difference in cancer survival. MR analysis supported a positive relationship between endometriosis and ovarian cancer (OR = 1.203, 95% CI: 1.011—1.433). The history of endometriosis was positively associated with the history of overall and ovarian cancer. Women with a history of endometriosis should have access to enhanced cancer surveillance and proactive management. Further research is needed to confirm these associations and to give mechanistic insights. Graphical Abstract

Construction of Metastasis-Specific Regulation Network in Ovarian Cancer Based on Prognostic Stemness-Related Signatures

WE aimed to reveal the correlation between ovarian cancer (OV) metastasis and cancer stemness in OV. RNA-seq data and clinical information of 591 OV samples (551 without metastasis and 40 with metastasis) were obtained from TCGA. The edgeR method was used to determine differentially expressed genes (DEGs) and transcription factors (DETFs). Then, mRNA expression-based stemness index was calculated using one-class logistic regression (OCLR). Weighted gene co-expression network analysis (WGCNA) was used to define stemness-related genes (SRGs). Univariate and multivariate Cox proportional hazard regression were conducted to identify the prognostic SRGs (PSRGs). PSRGs, DETFs, and 50 hallmark pathways quantified by gene set variation analysis (GSVA) were integrated into Pearson co-expression analysis. Significant co-expression interactions were utilized to construct an OV metastasis-specific regulation network. Cell communication analysis was carried out based on single cell RNA sequencing data to explore the molecular regulation mechanism of OV. Eventually, assay for targeting accessible-chromatin with high throughout sequencing (ATAC), chromatin immunoprecipitation sequencing (ChIP-seq) validation, and multiple data sets were used to validate the expression levels and prognostic values of key stemness-related signatures. Moreover, connectivity map (CMap) was used to identify potential inhibitors of stemness-related signatures. Based on edgeR, WGCNA, and Cox proportional hazard regression, 22 PSRGs were defined to construct a prognostic prediction model for metastatic OV. In the metastasis-specific regulation network, key TF-PSRS interaction pair was NR4A1-EGR3 (correlation coefficient = 0.81, p < 0.05, positive), and key PSRG-hallmark pathway interaction pair was EGR3-TNFα signaling via NFκB (correlation coefficient = 0.44, p < 0.05, positive), which were validated in multi-omics databases. Thioridazine was postulated to be the most significant compound in treatment of OV metastasis. PSRGs played critical roles in OV metastasis. Specifically, EGR3 was the most significant PSRG, which was positively regulated by DETF NR4A1, inducing metastasis via TNFα signaling.

Histologic Subtypes in Endometriosis-Associated Ovarian Cancer and Ovarian Cancer Arising in Endometriosis: A Systematic Review and Meta-Analysis

AbstractThe definition of the association between ovarian cancer and endometriosis was first reported by Sampson in 1925. He identified the following criteria: (a) clear evidence of endometriosis in proximity to the tumour, (b) exclusion of a metastatic tumour to the ovary, (c) presence of tissue resembling endometrial stroma surrounding epithelial glands. The naming of these cancers is “endometriosis-associated ovarian cancer” (EAOC). Scott proposed an additional stringent criterion: evidence of histological transition from endometriosis to cancer is to define “ovarian cancer arising in endometriosis” (OCAE). The aim of this systematic review is to analyse the distribution of different ovarian cancer histotypes in EAOC and OCAE to understand their similarities and differences. A total of 31 studies were included. Four studies added data for both EAOC and OCAE. Twenty-three studies were selected for EAOC, with a total of 800 patients, and 12 studies were selected for OCAE, with a total of 375 patients. The results show no significant differences in the distribution of histotypes in the two populations analysed. Clear cell carcinoma (CCC) and endometrioid carcinoma (EC) were the most common subtypes and were less frequent in EAOC compared to OCAE; the odd ratios were 0.58 (0.26–1.29) and 0.65 (0.33–1.26) respectively, although the difference was not statistically significant. The other histotypes were present in small proportions. This analysis shows that the histological profiles of EAOC and OCAE are similar, suggesting a similar aetiopathological mechanism, which requires further research to investigate whether EAOC and OCAE may be in the same way but at different points of the process to malignancy or have different pathways of progression to malignancy.

The Downregulation of MMP23B Facilitates the Suppression of Vitality and Induction of Apoptosis in Endometrial Cancer Cells

AbstractEndometrial cancer is a malignant tumor that commonly occurs in the female reproductive system and its incidence is still increasing. The mechanism of the development of endometrial cancer has not yet been fully clarified, so we need to continuously study the relevant mechanisms of endometrial cancer and continue to explore its biomarkers in order to discover more precise and effective treatment methods for endometrial cancer. RT-qPCR (Real-Time quantitative Polymerase Chain Reaction) experiments were used to detect the expression level of MMP23B (Matrix Metalloproteinase 23B) in endometrial cancer cells; the clinical data of the TCGA (The Cancer Genome Atlas) database were downloaded, and gene expression profiles were analyzed to investigate the correlation between MMP23B (Matrix Metalloproteinase 23B) and the survival prognosis of endometrial cancer, and functional enrichment analysis was performed on MMP23B (Matrix Metalloproteinase 23B) related genes. After silencing MMP23B (Matrix Metalloproteinase 23B), CCK8 (Cell Counting Kit-8), RT-qPCR (Real-Time quantitative Polymerase Chain Reaction), scratch assay, and transwell assay were used to detect cell viability, levels of apoptotic factors, migration rate, and invasion number of endometrial cancer, respectively. MMP23B (Matrix Metalloproteinase 23B) was highly expressed in endometrial cancer, which is closely related to a poor survival prognosis for endometrial cancer, and may act on endometrial cancer through apoptosis-related functions. The downregulation of MMP23B (Matrix Metalloproteinase 23B) reduced the cell viability of endometrial cancer cells, upregulated the expression levels of CASP3 (Caspase-3), CASP8 (Caspase-8) and CASP9 (Caspase-9) in cells, and inhibited cell migration and invasion.

The Efficacy of Ganoderma lucidum Extracts on Treating Endometrial Cancer: A Network Pharmacology Approach

AbstractGanoderma lucidum(GL) is a prominent medicinal mushroom in traditional Chinese medicine, known for its potent antitumor properties. This study aimed to illustrate the efficacy of GL extracts (GLE) on treating endometrial cancer (EC) and explore the underlying mechanisms via network pharmacology and experimental validation. Network pharmacological analysis was conducted to explore the therapeutic efficacy and mechanisms of GL on EC. In vitro experimental validation was performed on human endometrial cancer cell lines HEC-1-A and KLE. Network pharmacology revealed that key targets of GL against EC were primarily associated with the Rap1 signaling pathway. In in vitro experiments, GLE or GGTI-298 (a GTPase inhibitor) treatment inhibited cell proliferation and migration, promoted cell apoptosis, increased caspase-3 level, and arrested cell cycle in G1 phase in HEC-1-A and KLE cells. GLE increased the protein expression of Rap1-GTP, p-AKT, and p-ERK2 in HEC-1-A and KLE cells. Moreover, GGTI-298 enhanced the effects of GLE on suppressing the malignant progression of EC cells and on activating Rap1 signaling pathway. GLE inhibited the malignant progression of EC cells probably via activating the Rap1 signaling pathway.

17beta-estradiol (E2) Regulates Malignancies and Stemness in Endometrial Carcinoma (EC) via Interacting with ESR1

Abstract Endometrial cancer is one of the most common and fatal gynaecologic malignancies and is associated with the presence of estrogen. Endometrial cancer stem-like cells (ECSCs) are stem-like cell subpopulations endowed with self-renewal and differentiation capacities and are critical for EC progression. However, it is still unknown whether estrogen is involved in regulating stemness in EC and contributes to malignancies. Therefore, we investigated the regulatory effects of E2 treatment on oestrogen receptor-1 (ESR1). ESR1 expression was measured in EC tissues; After ESR1 overexpression of knockdown, the effects of E2 treatment was evaluated, including cell proliferation, sphere formation, invasion and colony formation. Our results indicate that ESR1 is critical for the regulatory effect of E2 on EC cells. After being cultured in serum-free medium, the ECSCs were found to be enriched in stemness markers, including CD133, CD44 and ALDH1. Interestingly, enriched ECSCs presented significantly lower expression levels of these factors than the parental cells. Overexpression of ESR1 slightly affected stemness and malignant potential in ECSCs, and the addition of 2 nM E2 markedly decreased stemness and inhibited malignant behaviours of ECSCs, including proliferation, invasion and tumour formation, in soft agar. Moreover, the addition of E2 significantly inhibited the expression of epithelial-mesenchymal transition (EMT) markers, including ZEB1, ZEB2, and E-cadherin. ESR1 is critical for regulating EC progression in the presence of E2, partially by regulating stemness in ECSCs, indicating that ESR1 might be a potential therapeutic target for EC.

The Effect of Endometrial Polyp and Myoma Uteri on Fertility-Related Genes in the Endometrium

Abstract Endometrial polyps are hyperplastic overgrowths of the endometrium that contain both glands and stroma. Myoma uteri is the most common benign tumor of the female pelvis and uterus. HOXA10, which is involved during the organogenesis of the uterus in the embryonic period. The aim of this study was to compare the expression levels of infertility-related genes in endometrial tissue obtained from patients with endometrial polyp and myoma uteri and from healthy controls. A total of 36 patients, including 15 women with endometrial polyp and 21 women with myoma uteri, and 23 healthy controls were enrolled in the study. All patients were evaluated using transvaginal ultrasonography. Endometrial tissue samples were collected from the patient and control groups between the 19th and 21st days of the menstrual cycle. Expression levels of the receptivity markers PROK1, PROKR1, PROK2, PROKR2 and HOXA10 genes were determined by RT- PCR. When the patients diagnosed with endometrial polyp and the healthy controls were compared, it was observed statistically significantly that the expression of PROKR1 increased in endometrium tissue of patients with endometrial polyp (p &lt; 0.05). In patients diagnosed with myoma uteri, gene expression levels of endometrial PROKR1 was statistically significant increased and gene expression levels of PROK1, PROKR2, HOXA10 were found to be statistically significantly decreased compared to the controls (p &lt; 0.05). Changes in the endometrial expression of the HOXA10 and prokineticin gene family in patients with myoma uteri and endometrial polyps may explain certain aspects of infertility in these patients.

Integrating Bioinformatics and Experimental Validation to Identify Mitochondrial Permeability Transition-Driven Necrosis-Related lncRNAs that can Serve as Prognostic Biomarkers and Therapeutic Targets in Endometrial Carcinoma

Abstract Endometrial carcinoma (EC) is a common malignant tumor in women with high mortality and relapse rates. Mitochondrial permeability transition (MPT)-driven necrosis is a novel form of programmed cell death. The MPT-driven necrosis related lncRNAs (MRLs) involved in EC development remain unclear. We aimed to predict the outcomes of patients with EC by constructing a novel prognostic model based on MRLs and explore potential molecular functions. A risk prognostic model was developed utilizing multi-Cox regression in conjunction with the Least Absolute Shrinkage and Selection Operator (LASSO) regression algorithm, which was based on MRLs. The predictive efficacy of the model was evaluated through receiver operating characteristic (ROC) curve analysis, as well as nomogram and concordance index (C-index) assessments. Patients were categorized into high- and low-risk groups based on their median risk scores. Notably, the high-risk group exhibited significantly poorer overall survival (OS) outcomes. Gene ontology (GO) and Gene set enrichment analysis (GSEA) demonstrated that Hedgehog and cell cycle pathways were enriched in the high-risk group. Tumor Immune Dysfunction and Exclusion (TIDE) displayed that patients in the high-risk group showed a high likelihood of immune evasion and less effective immunotherapy. A significant disparity in immune function was also observed between two groups. Based on the nine-MRLs, drug sensitivity analysis identified several anticancer drugs with potential efficacy in prognosis. Meanwhile, the results demonstrated that OGFRP1 plays a carcinogenic role by affecting mitochondrial membrane permeability in EC. Therefore, the risk model constructed by nine MRLs could be used to predict the clinical outcomes and therapeutic responses in patients with EC effectively.

Molecular Basis Supporting the Association of Talcum Powder Use with Increased Risk of Ovarian Cancer

Necroptosis-Related LncRNA Signatures for Prognostic Prediction in Uterine Corpora Endometrial Cancer

Abstract Necroptosis is one of the common modes of apoptosis, and it has an intrinsic association with cancer prognosis. However, the role of the necroptosis-related long non-coding RNA LncRNA (NRLncRNAs) in uterine corpora endometrial cancer (UCEC) has not yet been fully elucidated at present. Therefore, the present study is designed to investigate the potential prognostic value of necroptosis-related LncRNAs in UCEC. In the present study, the expression profiles and clinical data of UCEC patients were downloaded from TCGA database to identify the differentially expressed NRLncRNAs associated with overall survival. A LncRNA risk model was constructed via Cox regression analysis, and its prognostic value was evaluated. We have also further evaluated the relationships between the LncRNA features and the related cellular function, related pathways, immune status, and immune checkpoints m6A-related genes. Seven signatures, including PCAT19, CDKN2B-AS1, LINC01936, LINC02178, BMPR1B-DT, LINC00237, and TRPM2-AS, were established to assess the overall survival (OS) of the UCEC in the present study. Survival analysis and ROC curves indicated that the correlated signature has good predictable performance. The normogram could accurately predict the overall survival of the patients with an excellent clinical practical value. Enrichment analysis of gene sets indicated that risk signals were enriched in several immune-related pathways. In addition, the risk characteristics were significantly correlated with immune cells, immune function, immune cell infiltration, immune checkpoints, and some m6A-related genes. This study has identified seven necroptosis-related LncRNA signatures for the first time, providing a valuable basis for a more accurate prognostic prediction of UCEC.

Heat Shock Protein 60 (HSP60) Serves as a Potential Target for the Sensitization of Chemoresistant Ovarian Cancer Cells

HSP60 is a mitochondrial chaperone protein that is associated with decreased overall survival of ovarian cancer patients. We determined whether targeting HSP60 with its monoclonal antibody would induce cytotoxicity in sensitive and chemoresistant ovarian cancer cells and whether it is synergistic when combined with chemotherapeutic drugs. Epithelial ovarian cancer (EOC) cells and their docetaxel- or cisplatin-resistant counterparts were utilized. HSP60 mRNA levels were determined by real-time RT-PCR. Cytotoxicity of HSP60 antibody (0.5 or 1.5 μg/ml) alone and in combination with chemotherapy were assessed by MTT Cell Proliferation Assay. Unpaired t tests were used to compare groups for real-time RT-PCR. One-way ANOVA followed by Tukey's post hoc tests with Bonferroni correction was performed for cytotoxicity comparisons. Significant synergistic effects of the antibody combined with chemotherapy were determined by the CompuSyn Software. Basal HSP60 mRNA levels were increased in chemoresistant EOC cells as compared with their sensitive counterparts (p < 0.05). There was no significant difference in cytotoxicity between EOC cell types; however, treatment with the HSP60 antibody for 24 h showed a dose response (0.5 and 1.5 μg/ml) cytotoxic effect to both sensitive and chemoresistant EOC cells as compared with the isotype control (p < 0.05). Importantly, treatment with both doses of HSP60 antibody was not cytotoxic to normal macrophages. Combination of the HSP60 antibody with docetaxel or cisplatin was significantly synergistic in both sensitive and chemoresistant EOC cells. Here, we identify a novel target that may serve not only for ovarian cancer treatment but also for sensitization of patients to chemotherapy. The cytotoxic effect of HSP60 monoclonal antibody and its synergism with chemotherapeutic agents highlight HSP60 as a promising target for therapy and chemosensitization in ovarian cancer treatment.

miR-205-3p Functions as a Tumor Suppressor in Ovarian Carcinoma

Ovarian cancer (OC) represents the most lethal form of gynaecologic cancers in developed countries. To develop a better therapeutic against OC, characterizing new classes of molecular regulators such as microRNAs (miRNAs) involved in OC tumorigenesis becomes immensely important. We used human OC cell lines to study the expression pattern of miRNA-205-3p. We then employed miRNA-205-3p mimic and inhibitor to elucidate its functional role in OC cells. Downstream target of miRNA-205-3p was characterized in OC cells with luciferase gene reporter assay and Western blotting. Its functional role in OC was also investigated with the siRNA approach. Lastly, we assessed the expression change of miRNA-205-3p and its newly identified target in human OC tissues. miR-205-3p was downregulated in five human OC lines tested. Over-expressing miR-205-3p reduced OC cell proliferation and migration. MAPK10 was identified as a direct target of miR-205-3p. Knocking down MAPK10 suppressed OC cell growth and migration. In contrast, knocking down miR-205-3p promoted clonogenicity of primary ovary cells. In clinical samples, miR-205-3p and MAPK10 expressed inversely in accordance with their expression patterns in OC cells. miR-205-3p was shown as a novel tumor suppressor in OC via inhibiting the MAPK10 pathway. This new finding may inspire new personalized treatment for OC.

Differential Expression of KRAS and SIRT1 in Ovarian Cancers with and Without Endometriosis

Accumulating research shows that ovarian cancer progression can be influenced by both gene mutations and endometriosis. However, the exact mechanism at hand is poorly understood. In the current study, we explored the expression of KRAS and SIRT1, two genes previously identified as altered in endometriosis and ovarian cancer. Human endometrial samples were obtained from regularly cycling women with endometriosis, ovarian cancer, and endometriosis-associated ovarian cancer between 18 and 50 of age undergoing hysterectomy, and immunohistochemical analyses were performed. The cytoplasmic expression of KRAS was low in eutopic endometrium from women without endometriosis or ovarian cancer; however, it was elevated in those who have been diagnosed with endometriosis, as well as ovarian cancer with or without the presence of endometriosis. Nuclear and cytoplasmic SIRT1 expression was also low within endometrium without either disease. However, nuclear SIRT1 expression was increased in those with endometriosis and ovarian cancer associated with endometriosis. Nuclear but not the cytoplasmic expression of SIRT1 correlated with KRAS expression in ovarian cancers associated with endometriosis. These results suggest roles of KRAS and SIRT1 in endometriosis and endometriosis-associated ovarian cancer. Cytoplasmic KRAS expression proves to be a key biomarker in both diseases, while nuclear SIRT1 may be a new biomarker specific to those with endometriosis and those with both endometriosis and ovarian cancer. Further research of these genes could aid in determining the pathogenesis of both diseases and help in clarifying the development of endometriosis-associated ovarian cancer.

Long Non-coding RNA NEAT1 as an Emerging Biomarker in Breast and Gynecologic Cancers: a Systematic Overview

Long non-coding RNAs (lncRNAs) are emerging regulators of cellular pathways, especially in cancer development. Among the lncRNAs, nuclear paraspeckle assembly transcript 1 (NEAT1) forms a scaffold for a nuclear body; the paraspeckle and aberrant expression of NEAT1 have been reported in breast and gynecologic cancers (ovarian, cervical, endometrial, and vulvar). Abundantly expressed NEAT1 in breast and gynecologic cancers generally contribute to tumor development by sponging its corresponding tumor-suppressive microRNAs or interacting with various regulatory proteins. The distinct expression of NEAT1 and its contribution to tumorigenic pathways make it a promising therapeutic target in breast and gynecologic cancers. Herein, we summarize the functions and molecular mechanisms of NEAT1 in human breast, ovarian, cervical, endometrial, and vulvar cancers. Furthermore, we emphasize its critical role in the formation of paraspeckle development and its functions. Conclusively, NEAT1 is a considerable biomarker with a bright prospect and can be therapeutically targeted to manage breast and gynecologic cancers.

Dissecting the Single-Cell Diversity and Heterogeneity Underlying Cervical Precancerous Lesions and Cancer Tissues

Abstract The underlying cellular diversity and heterogeneity from cervix precancerous lesions to cervical squamous cell carcinoma (CSCC) is investigated. Four single-cell datasets including normal tissues, normal adjacent tissues, precancerous lesions, and cervical tumors were integrated to perform disease stage analysis. Single-cell compositional data analysis (scCODA) was utilized to reveal the compositional changes of each cell type. Differentially expressed genes (DEGs) among cell types were annotated using BioCarta. An assay for transposase-accessible chromatin sequencing (ATAC-seq) analysis was performed to correlate epigenetic alterations with gene expression profiles. Lastly, a logistic regression model was used to assess the similarity between the original and new cohort data (HRA001742). After global annotation, seven distinct cell types were categorized. Eight consensus-upregulated DEGs were identified in B cells among different disease statuses, which could be utilized to predict the overall survival of CSCC patients. Inferred copy number variation (CNV) analysis of epithelial cells guided disease progression classification. Trajectory and ATAC-seq integration analysis identified 95 key transcription factors (TF) and one immunohistochemistry (IHC) testified key-node TF (YY1) involved in epithelial cells from CSCC initiation to progression. The consistency of epithelial cell subpopulation markers was revealed with single-cell sequencing, bulk sequencing, and RT-qPCR detection. KRT8 and KRT15, markers of Epi6, showed progressively higher expression with disease progression as revealed by IHC detection. The logistic regression model testified the robustness of the resemblance of clusters among the various datasets utilized in this study. Valuable insights into CSCC cellular diversity and heterogeneity provide a foundation for future targeted therapy.

E2F8 Transcriptionally Activates DTL to Promote Endometrial Cancer Progression Via the MAPK Pathway

E2F family transcription factors are involved in various cancers, yet the role of E2F transcription factor 8 (E2F8) in endometrial cancer (EC) remains elusive. This study explores how E2F8 transcriptionally activates denticleless E3 ubiquitin protein ligase homolog (DTL) to promote EC progression via the MAPK signaling. Bioinformatic analysis of the GEO dataset GSE63678, along with GEPIA2, AnimalTFDB v4, and ChIP-Atlas, identified E2F8 and its potential target DTL in EC. Elevated expression of E2F8 and DTL was confirmed in EC tissues, which correlated with a higher International Federation of Gynecology and Obstetrics stage. Functional assays demonstrated that E2F8 knockdown suppressed EC cell proliferation, migration, invasion, and MAPK pathway activation, while DTL overexpression or PDCD4 knockdown reversed these effects. Knockdown of DTL enhanced PDCD4 ubiquitination. In vivo, silencing of E2F8 inhibited tumor growth in EC xenograft models, whereas DTL upregulation or PDCD4 knockdown restored tumor progression and enhanced MAPK pathway activity and Ki67 expression. In conclusion, E2F8 promotes EC progression by transcriptionally activating DTL and activating the MAPK pathway. These findings provide novel mechanistic insights into EC progression and suggest that the E2F8/DTL/PDCD4/MAPK axis may serve as a potential therapeutic target for EC.

The Role of Four New Biochemical Markers in the Diagnosis and Prognosis of Ovarian Carcinoma

This study aimed to assess the diagnostic and prognostic value of four biochemical markers-PAX9, HK10, TBX2, and CYFRA21-1-in ovarian carcinoma (OC). We conducted a prospective diagnostic study from December 2020 to December 2021, enrolling 88 patients with ovarian carcinoma, 90 with benign ovarian lesions, and 92 healthy controls. Blood levels of HK10 and CYFRA21-1 were measured, while tissue expressions of PAX9 and TBX2 were analyzed. We used logistic regression and ROC curve analysis to evaluate the diagnostic performance of these markers. The OC group showed significantly higher positive expression rates of PAX9 and TBX2 compared to the benign group (65.91% vs. 4.44% and 26.14% vs. 3.33%, respectively). Additionally, HK10 and CYFRA21-1 levels were significantly elevated in the OC group compared to both the benign and healthy groups (P < 0.05). The expressions of all four markers were closely associated with clinical parameters such as tumor diameter, FIGO stage, degree of differentiation, and lymph node metastasis (P < 0.05). The sensitivity and specificity value of CA125, HK10, CYFRA21-1, PAX9, and TBX2 in the diagnosis of ovarian cancer were 85.09% and 80.09%, 65.87% and 61.67%, 81.25% and 79.59%, 75.32% and 74.49%, and 61.46% and 69.39%, respectively. The sensitivity and specificity of the combined biomarkers diagnosis are respectively 87.59% and 84.69%. The combined assessment of PAX9, HK10, TBX2, and CYFRA21-1 provides significant diagnostic and prognostic value in ovarian carcinoma, with HK10 showing particularly high sensitivity. These markers could play a crucial role in the early detection and management of ovarian carcinoma.

m5C-Modified lncRNA SNHG15 Promotes Ovarian Cancer Progression Via the miR-545-3p/PD-L1 Axis

Ovarian cancer (OC) poses a health burden of women. Long non-coding RNA SNHG15 has been reported to promote OC progression; however, its effect on immune evasion remains unknown. Here, we investigated the effect of SNHG15 on OC cell immune evasion and the underlying mechanism. Cell phenotypes were assessed using cell counting kit-8, colony formation, lactate dehydrogenase cytotoxicity, and enzyme-linked immunosorbent assays. The mechanism was evaluated by dual-luciferase reporter assay, RNA pull-down, RNA immunoprecipitation (RIP), methylated RIP, and RNA stability assay. The role in vivo was analyzed using tumor-bearing mice. The results showed that SNHG15 and PD-L1 levels were increased, while miR-545-3p expression was reduced in OC. SNHG15 was a sponge of miR-545-3p, and PD-L1 was a downstream target of SNHG15. Knockdown of SNHG15 suppressed OC cell proliferation, and enhanced cytotoxicity and pro-inflammatory response of CD8

Evaluation of the In Vivo Efficacy of the JAK Inhibitor AZD1480 in Uterine Leiomyomas Using a Patient-derived Xenograft Murine Model

Uterine leiomyomas are common noncancerous hormonally-dependent neoplasms comprised of uterine smooth-muscle cells and fibroblasts. Despite their significant impact on morbidity, effective non-hormonal medical treatments are lacking. In vitro studies have identified the Janus kinase/signal transducer and activator of transcription (JAK/STAT) signaling pathway as a promising target in leiomyoma cells. Our objective was to evaluate the efficacy of AZD1480, a JAK 1/2 inhibitor, in treating uterine leiomyomas using a patient-derived xenograft murine model. Ovariectomized immunodeficient mice received an estrogen and progesterone pellet and were subsequently implanted with human leiomyoma tissue surgically resected from premenopausal women not on hormonal medication. Mice were divided into treatment (n = 6) and vehicle control (n = 6) groups receiving either 50 mg/kg of AZD1480 or vehicle via oral gavage for 5 days/week for 28 days. Our results demonstrate a significant AZD1480-mediated reduction in both xenograft volume (59.5% vs. 0.3%; treated vs. control, p < .0001) and weight (56.0% vs. 31.2%; p = 0.03) compared to controls. Moreover, xenografts from the treated group exhibited a significant decrease in cell density(p = 0.01). Levels of pSTAT3-positive cells (4.1% vs. 10.3%), Ki67-positive cells (4.1% vs. 6.5%), and fibrillar collagen (19.8% vs. 29.5%) declined but did not reach statistical significance, whereas AZD1480 treatment significantly reduced blood vessel formation in the xenografts (20.1 vs 45.6 per FOV; p = 0.01). These findings suggest JAK inhibition as a potential treatment for uterine leiomyomas by targeting angiogenesis. However, further studies are warranted to explore alternative JAK inhibitors, examine downstream effects, optimize dosing, and establish clinical efficacy and safety.

Cancer-associated Fibroblasts-derived Exosomes with HOXD11 Overexpression Promote Ovarian Cancer Cell Angiogenesis Via FN1

Cancer-associated fibroblasts (CAFs) represent a critical stromal component of metastatic niche and promote metastasis in patients with ovarian cancer (OC). Here, we try to further understand the mechanism by which CAFs-derived exosomes (CAFs-Exo) promoted angiogenesis in OC. We intersected differentially expressed genes in OC cells after CAFs-Exo treatment in the GSE147610 dataset with a list of transcription factors to identify homeobox protein hox-D11 (HOXD11) as a possible cargo of CAFs-Exo. HOXD11 encapsulated by CAFs-Exo enhanced colony formation, migration, and invasion of OC cells. HOXD11 bound to the promoter of fibronectin (FN1) and promoted its transcription. HOXD11 knockdown from CAFs-Exo significantly repressed the VEGF and CD31 protein expression and tube formation, viability, and migration of human umbilical vein endothelial cells (HUVEC) and slowed angiogenesis and tumor growth in mice. Furthermore, we found that overexpression of FN1 increased the expression of angiogenic factors and activity of HUVEC in the presence of HOXD11 knockdown. These results verify the significant contribution of CAFs-Exo to angiogenesis in OC, which could be partially due to the promotion of FN1 mediated by HOXD11.

ERBB2 Targeting Reveals a Significant Suppression of Tumorigenesis in Murine Endometrial Cancer with Pten Mutation

Endometrial cancer is the most common gynecologic malignancy. PTEN is a negative regulator of PI3K signaling and is deficient in > 50% of primary human endometrial cancer. Amplification of ERBB2 promotes tumorigenesis and pathogenesis of several human cancers. However, the effect of ERBB2 targeting has not been studied in endometrial cancer with PTEN mutations. The murine model Pgr

Dysgerminoma Probably Due to a Novel SOHLH1-pathogenic Variant Causing Familial Ovarian Dysgenesis

Pathogenic variants of the SOHLH1 gene are responsible for an autosomal recessive form of ovarian dysgenesis; this gene encodes a transcription factor expressed early in spermatogonia and oocytes and contributes to folliculogenesis. Previously, four affected women from two unrelated families reported homozygous variants in the SOHLH1 gene, but none had a history of gonadal malignancy or a histologic description. We present two sisters and their paternal great-aunt with a history of primary amenorrhea, pubertal delay, and hypergonadotrophism who came from an inbred Mexican family. The proband was the younger sister who was referred for bilateral dysgerminoma. She had a normal blood karyotype, and whole-exome sequencing analysis revealed a novel homozygous missense variant, c.275C>T, in SOHLH1; several family members were also analyzed. In addition to pure dysgerminoma, histopathological analysis revealed an ovarian cortex with fibrosis and almost total absence of follicles. This work confirms the inheritance of ovarian dysgenesis 5, supports the occurrence of cell loss in mouse models, and suggests that affected women should undergo periodic imaging surveillance due to the likely risk of tumor development.

ARG1 Is a Potential Prognostic Marker in Metastatic Endometrial Cancer

Endometrial cancer (EC) is the most common gynecologic malignancy. While the majority of patients present with early-stage and low-grade EC and have an excellent prognosis, a subset has metastatic disease at presentation or develops distant recurrence after initial treatment of the primary. However, the lack of prognostic biomarkers for metastatic EC is a critical barrier. Arginase 1 (ARG1) regulates the last step of the urea cycle, and an increase in ARG1 has been correlated as a poor prognostic factor in a variety of cancers. In the present study, ARG1 expression was evaluated as a potential prognostic marker for metastatic EC in endometrial hyperplasia and cancer of mice with Pten mutation as well as Pten and Mig-6 double mutations. While Pten mutation in the uterus is not sufficient for distant metastasis, mice with concurrent ablation of Mig-6 and Pten develop distant metastasis. Our immunostaining and RT-qPCR analysis revealed that the expression of ARG1 in early stage of EC as well as endometrial hyperplasia from mice deficient in Mig-6 and Pten mutations significantly increased compared to Pten mutation in the uterus. The results suggest that a high level of ARG1 is associated with poor prognosis in association with EC of mouse.

Psychosocial Stress and MicroRNA Expression Profiles in Myometrial Tissue of Women Undergoing Surgical Treatment for Uterine Fibroids

Uterine leiomyomas (fibroids) are the most common non-cancerous tumors affecting women. Psychosocial stress is associated with fibroid risk and severity. The relationship between psychosocial stress and fibroid pathogenesis may involve alterations in microRNAs (miRNAs) although this has yet to be examined. We investigated associations between two psychosocial stress measures, a composite measure of recent stressful life events and perceived social status, with expression levels of 401 miRNAs in myometrium (n = 20) and fibroids (n = 44; 20 with paired fibroid and myometrium samples) among pre-menopausal women who underwent surgery for fibroid treatment. We used linear regressions to identify psychosocial stressors associated with miRNAs, adjusting for covariates (age, body mass index, race/ethnicity, and oral contraceptive use). The association between psychosocial stressors and miRNAs was considered statistically significant at an FDR p < 0.10 and showed a monotonic response (nominal p-trend < 0.05). In the myometrium, 21 miRNAs were significantly associated with a composite measure of recent stressful events, and two miRNAs were associated with perceived social status. No fibroid miRNAs were associated with either stress measure. Pathway analyses revealed miRNA-mRNA targets were significantly enriched (FDR p < 0.05) in pathways relevant to cancer/tumor development. Of the 74 differentially expressed miRNAs between myometrium and fibroids, miR-27a-5p and miR-301b were also associated with stress exposure. Our pilot analysis suggests that psychosocial stress is associated with myometrial miRNA expression and, thus, may have a role in the pathogenesis of fibroids from healthy myometrium.

Fertility-Sparing Surgery and Adjuvant Chemotherapy with Trastuzumab Result in Complete Remission in a Young Woman with Rare Primary Mucinous Ovarian Cancer due to ERBB2 Co-amplification with CDK12 and Chromosome 11q13.3 Amplicon: A Case Report and Literature Review

Primary mucinous ovarian carcinoma (PMOC) is a rare tumor, accounting for approximately 3% of all epithelial ovarian cancers (EOCs), with clinical risk factors and biologic features distinct from that of EOC. The prognosis for women with recurrent and high-grade PMOC remains poor, likely related to a poor response to conventional chemotherapy for EOC. A 27-year-old Chinese woman sought medical attention in January 2021 for abdominal distention from a large pelvic mass. After extensive investigations and workup, she was diagnosed with PMOC of the right ovary. Following multidisciplinary team (MDT) discussions, the patient underwent fertility-sparing surgery (FSS) (abdominal left adnexectomy, right partial oophorectomy, pelvic lymph node dissection, para-aortic lymph node dissection, omentectomy) as she yearned to preserve her fertility and the contralateral ovary appeared normal. Deep genetic analyses revealed ERBB2 co-amplification with CDK12 and chromosome 11q13.3 amplicon. Treatment with fertility-sparing surgery and adjuvant chemotherapy with trastuzumab results in complete remission. This novel strategy utilizing precise diagnostics and characterization of the histo-type of rare tumors allowed personalized targeting with optimum drug response for women who yearn fertility preservation and remission from the disease, especially when there is very limited clinical experience on management of such rare ovarian tumors.

Evaluation of Safety and Efficacy of Amniotic Mesenchymal Stem Cells for POI in Animals

The efficacy of human amniotic mesenchymal stem cell (hAMSC) ovarian injection in improving ovarian function in primary ovarian insufficiency (POI) patients has been shown in some reports. However, the safety and efficacy of hAMSC vein injection remains unclear. In this study, we evaluated the safety and efficacy of hAMSC intravenous injection in cynomolgus macaques and SD rats and provided evidence for clinical trials. The hAMSCs were transplanted three times in SD rats at low, medium, and high doses. The animal behavior and biochemical and biophysical parameters were routinely monitored on a 2-month period posttransplantation, and histopathologic examinations were also performed. Experiments on the acute toxicity, allergy test, and hemolysis test showed that hAMSCs possess good biocompatibility. Our results showed that the maximum tolerated dose of hAMSCs in SD rats was 4.0 × 10

Recurrence of Uterine Fibroids After Conservative Surgery or Radiological Procedures: a Narrative Review

The present narrative review aims to discuss the available data on the incidence and the risk factors of uterine fibroids (UFs) recurrence after different types of conservative surgical or radiologic procedures in women wishing to preserve their uterus. UFs are the most common benign tumors in women all over the world. Clinical presentation, including abnormal uterine bleeding (AUB), pelvic pain, bulky symptoms, and infertility affect patients' quality of life, and a large variety of conservative treatments are available especially for those with desire of pregnancy. Fertility sparing surgery, by either laparoscopy, hysteroscopy or laparotomy, or radiological interventions (uterine artery embolization, high-intensity focused ultrasound or magnetic resonance-guided focused ultrasound), are the most common therapeutic approaches. However, the genetic or acquired predisposition to UFs remain despite the treatments, and the recurrences are frequently described in a large percentage of patients. The most relevant risk factors for recurrence of UFs are young age at the first surgery, incomplete fibroid resection, the presence of multiple lesions, an enlarged uterus, and the coexistence with other pelvic diseases. The discussion on the possible medical strategy to reduce the recurrence is an open field of clinical investigation, in particular by using hormonal drugs.

Survival Impact of Sentinel Lymph Node Biopsy in Patients with Early-Stage Cervical Cancer

To assess whether there were statistically significant differences in terms of overall survival (OS) and progression-free survival (PFS) between pelvic lymphadenectomy (PL) and sentinel lymph node biopsy (SLNB) alone as a nodal assessment method in patients with early-stage cervical cancer (IA1 with ILV to IB2 or IIA1 of the FIGO 2018 classification). A retrospective study was conducted among patients with early-stage cervical cancer who underwent radical surgery with pelvic lymph node assessment at La Paz University Hospital between 2005 and 2022. For nodal staging, either PL, SLNB + PL, or exclusive SLNB were performed, depending on the time period. Kaplan-Meier survival curves were compared between the PL and SLNB groups. Predictors of bilateral sentinel lymph node (SLN) detection were identified with Cox proportional hazard models. Among the 128 patients included, PL ± SLNB was performed in 79 (61.7%) patients and exclusive SLNB in 49 (38.3%) patients. There was no difference between PL and SLNB in OS (log-rank 0.0730) or PFS (log-rank 0.0189). Lower limb lymphedema (LLL) was significantly lower in the SLNB group (p = 0.001). Pelvic nodal assessment with SLNB alone did not worsen survival rates compared with the standard PL in patients with early-stage cervical cancer, and it is associated with a lower rate of LLL.

The Role of Bone Morphogenetic Protein 4 in Ovarian Function and Diseases

Bone morphogenetic proteins (BMPs) are the largest subfamily of the transforming growth factor-β (TGF-β) superfamily. BMP4 is a secreted protein that was originally identified due to its role in bone and cartilage development. Over the past decades, extensive literature has indicated that BMP4 and its receptors are widely expressed in the ovary. Dysregulation of BMP4 expression may play a vital role in follicular development, polycystic ovary syndrome (PCOS), and ovarian cancer. In this review, we summarized the expression pattern of BMP4 in the ovary, focused on the role of BMP4 in follicular development and steroidogenesis, and discussed the role of BMP4 in ovarian diseases such as polycystic ovary syndrome and ovarian cancer. Some studies have shown that the expression of BMP4 in the ovary is spatiotemporal and species specific, but the effects of BMP4 seem to be similar in follicular development of different species. In addition, BMP4 is involved in the development of hyperandrogenemia in PCOS and drug resistance in ovarian cancer, but further research is still needed to clarify the specific mechanisms.

LncRNA HOXC-AS3 Suppresses the Formation of Mature miR-96 in Ovarian Cancer Cells to Promote Cell Proliferation

HOXC-AS3 has been reported to be an oncogenic lncRNA in several types of cancer, while its role in ovarian cancer (OC) is unknown. This study aimed to explore the involvement of HOXC-AS3 in OC. The expression levels of HOXC-AS3, mature miR-96, and miR-96 precursor (premature miR-96) in OC and paired non-tumor tissues from 62 OC patients were determined by RT-qPCR. Correlations were analyzed by linear regression. The expression levels of mature miR-96 and miR-96 precursor in OC cells with the overexpression of HOXC-AS3 were determined by RT-qPCR. The roles of HOXC-AS3 and mature miR-96 in regulating the proliferation of OC cells were explored by CCK-8 assay. HOXC-AS3 was upregulated in OC, while mature miR-96 and miR-96 precursor were downregulated in OC. In OC tissues, HOXC-AS3 was inversely correlated with mature miR-96, but not miR-96 precursor. In OC cells, overexpression of HOXC-AS3 reduced the expression levels of mature miR-96, but not miR-96 precursor. Cell proliferation analysis showed that overexpression of HOXC-AS3 resulted in increased cell proliferation, while overexpression of miR-96 suppressed cell proliferation. In addition, overexpression of HOXC-AS3 attenuated the effects of overexpression of miR-96. HOXC-AS3 suppresses the formation of mature miR-96 in OC cells to promote cell proliferation.

Clinicopathological Characteristics and Prognosis of 91 Patients with Seromucinous and Mucinous Borderline Ovarian Tumors: a Comparative Study

To explore the differences in clinicopathological characteristics and prognosis between seromucinous borderline ovarian tumors (SMBOTs) and mucinous borderline ovarian tumors (MBOTs). Ninety-one patients with SMBOTs and MBOTs who underwent surgery at the Obstetrics and Gynecology Hospital of Fudan University from July 2006 to January 2015 were included. The median onset age of patients with SMBOTs (29 years, 20-77) was younger than that of patients with MBOTs (37 years, 16-71). SMBOTs were more likely to be exogenous and show bilateral ovarian involvement and had a smaller average tumor size of 10.63 cm, while MBOTs were more prone to endogenous growth and show unilateral involvement and had a larger average tumor size of 18.55 cm (p < 0.05). Compared with MBOTs, SMBOTs were characterized by the expression of Mullerian differentiation markers (p < 0.05). Recurrence occurred in 15.8% patients with SMBOT and 9.1% patients with MBOT. One case of SMBOT (2.6%) and one case of MBOT (2.3%) progressed to malignancy during follow-up, but no disease-related death was observed. Age less than 40 years was a risk factor for recurrence, while the effect of fertility-sparing surgery (FSS) on recurrence requires a larger sample size to be validated. The clinical characteristics of SMBOTs and MBOTs are similar but also quite different. High expression of Mullerian differentiation markers in SMBOT may indicate a better response to hormone therapy. Repeated FSS should be performed with caution and fully informed because of the risk of recurrence and progression to malignancy.

Seromucinous and Mucinous Borderline Ovarian Tumors: We Need to Know More

Borderline ovarian tumor (BOT) is a heterogeneous group of tumors characterized by low malignant potential and atypical proliferation, consisting of 15-20% of all primary ovarian neoplasm. Among BOTs, a subset has a high tendency of relapse probably due to inaccurate subtype stratification and unoptimized care. In this issue of Reproductive Sciences, Wu et al. compared two main BOT subtypes, seromucinous borderline (SMBOT), and mucinous borderline ovarian tumor (MBOT) across many aspects of their clinical pathological features, and identified significant different including tumor growth pattern, tumor sizes, recurrence rate, and the expression Mullerian markers. We reviewed similar work on features of BOT subtypes and highlighted the values added by this study. Future work could be validation with a larger sample size and multicenter design and the application of the identified difference in informing diagnosis and tailored treatment.

Molecular Features, Prognostic Value, and Cancer Immune Interactions of Angiogenesis-Related Genes in Ovarian Cancer

Angiogenesis is crucial to tumor growth and metastasis; it plays a key role in various cancers development and progression. However, the potential effects of angiogenesis-related genes (ARGs) in ovarian cancer (OC) remain to be further investigated. We discussed the characteristics changes of ARGs in 784 OC samples from genomic and transcriptional levels, as well as their expression patterns based on four distinct datasets. First, 784 OC patients were divided into three molecular subtypes, and the findings indicated that ARG changes were correlated with clinicopathological parameters, prognosis, and immune cell-infiltrating tumor microenvironment (TME). OC patients were subsequently divided into two gene subtypes depending on differentially expressed genes (DEGs) of the abovementioned molecular subtypes. We also established an ARGs-related score (ARGs score) model for evaluating overall survival (OS) and determining the immunological landscape of OC patients, therefore predicting patients' prognosis and therapeutic responses. A lower ARGs' score accompanied by a high mutation frequency implies a higher probability of survival. Furthermore, the ARG score was correlated with the cancer stem cell (CSC) index and chemotherapeutic sensitivity. The significant involvement of ARGs in the tumor-immune-stromal microenvironment, clinicopathological characteristics, and prognosis were established in our systematic investigation of ARGs for OC patients. These discoveries might help us to better understand the role of ARGs in OC, as well as give new insight for predicting the prognosis and providing promising immunotherapy.

Low-Nutrient Environment-Induced Changes in Inflammation, Cell Proliferation, and PGC-1α Expression in Stromal Cells with Ovarian Endometriosis

Although nutrient status plays an important role in cell metabolism, its significance in endometriosis is obscure. Herein, we investigated the effects of a low-nutrient microenvironment on endometriosis. Stromal cells (SCs) from ovarian endometrioma (OESCs) or normal endometrium without endometriosis (NESCs) were isolated and cultured. A low-nutrient microenvironment was replicated by replacing the culture medium with Hank's balanced salt solution. OESC and NESC proliferation under the low-nutrient condition was measured. The expression of exacerbating factors in endometriosis under the low-nutrient condition was examined at the mRNA and protein levels. OESCs showed higher proliferation than NESCs under the low-nutrient condition. In OESCs, the low-nutrient condition upregulated the mRNA expression of vascular endothelial growth factor (VEGF), interleukin-6 and -8, aromatase, Bcl-2, and peroxisome proliferator-activated receptor-gamma coactivator-1α (PGC-1α) and downregulated that of BAX and induced transcription of PI.3, PII, and exon II. Western blotting revealed elevated VEGF and PGC-1α expression under the low-nutrient condition in OESCs. These changes coincided with the elevated expression of PGC-1α, which was reduced at the mRNA level upon nutrient status rescue. Endometriosis is exacerbated by altered angiogenesis, inflammation, anti-apoptosis, and local estrogen production while trying to survive under a low-nutrient microenvironment; it may be attributed to PGC-1α-mediated metabolic mechanisms.

Platinum Resistance After PARPi Resistance in a gBRCAmt Recurrent Ovarian Cancer Patient: a Case Report

As the most lethal gynecological malignant tumor, ovarian cancer is prone to recurrence and drug resistance. Poly(ADP-ribose) polymerase inhibitors are known to be effective in ovarian cancer patients as maintenance treatment, especially in patients with BRCA mutation. The current controversy is whether the use of poly(ADP-ribose) polymerase inhibitors may affect subsequent platinum sensitivity. A Chinese female patient diagnosed with high-grade serous ovarian cancer experienced five platinum-sensitive relapses. After obtaining informed consent from the patient, we performed next-generation gene sequencing and detected a germline BRCA1 pathologic mutation. When the patient achieved partial response with platinum after the fifth platinum-sensitive relapse, exploratory posterior-line maintenance therapy was performed due to her genotype. But the patient rapidly progressed to platinum resistance after poly(ADP-ribose) polymerase inhibitor resistance. In a gBRCAmt patient with platinum-sensitive recurrent ovarian cancer, olaparib as exploratory posterior-line maintenance treatment is barely effective and may affect the response to subsequent platinum therapy.

mRNA, lncRNA and Circular RNA Expression Profiles in Granulosa Cells of Infertile Women with Ovarian Endometriosis

To explore the expression profiles of mRNAs, long-noncoding RNAs (lncRNAs), circular RNAs (circRNAs) and construct the competitive endogenous RNA networks in granulosa cells (GCs) of infertile women with ovarian endometriosis. RNA sequencing was conducted for RNA expression profiling from GCs of five women with ovarian endometriosis and five with tubal factor infertility. The differential expression of mRNAs, lncRNAs and circRNAs was compared. Then, the lncRNA-miRNA-mRNA and circRNA-miRNA-mRNA networks were constructed. Finally, the Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway were performed to determine the role of the differential expression of mRNA. A total of 12,498 mRNAs, 724 lncRNAs and 2269 circRNAs were identified in ovarian endometriosis and controls. 37 mRNAs, 51 lncRNAs and 101 circRNAs were detected to be differentially expressed in women with ovarian endometriosis. Ten lncRNAs and 22 differentially expressed mRNAs were selected to build the lncRNA-miRNA-mRNA network, while 12 circRNAs and four differentially expressed mRNAs were selected to build the circRNA-miRNA-mRNA network. GO analysis suggested that the differentially expressed mRNAs were mainly involved in regulation of cell differentiation, cell cycle while KEGG pathway analysis showed that pathways involved in the MAPK signaling pathway and FoxO signaling pathway were enriched with differentially upregulated mRNAs. We generated mRNAs, lncRNAs and circRNAs expression profiles and identified differentially expressed RNAs of GCs in infertile women with ovarian endometriosis. These findings provide a basis for further understanding of the underlying etiology of endometriosis-related infertility.

The Role of miRNA in Ovarian Cancer: an Overview

AbstractOvarian cancer (OC) is a highly malignant disease that seriously threatens women’s health and poses challenges for clinicians. MicroRNAs (miRNAs) have recently been intensively studied in the field of oncology due to their regulatory roles in gene expressions through RNA degradation and/or translation inhibition. This review summarizes the current studies on miRNAs in OC and introduces the latest updates of miRNAs in the early screening, treatment, and prognostic prediction of OC, thereby demonstrating the clinical significance of miRNAs in OC. Further exploration on potential targets of miRNAs in OC may provide new insights on optimizing the diagnosis and treatment of OC. MiRNAs are important driving factors for the progression of OC and the dysregulation of miRNAs can serve as biomarkers in the diagnosis, treatment and prognosis of OC. Therefore, miRNAs are potential biological targets for early screening, targeted therapy, drug resistance monitoring, and prognosis improvement in malignancies such as OC.

Aberrant Methylation of the SOX21-AS1 Promoter Region Promotes Gene Expression and Its Clinical Value in Cervical Cancer

Cervical cancer is the fourth most common female cancer worldwide. Long non-coding RNAs (lncRNAs), such as SOX21-AS1, play pivotal roles in the progression and metastasis of cancer. We previously described that SOX21-AS1 was hypomethylated in cervical cancer (CC) and aimed to further explore the relationship between methylation of the SOX21-AS1 promoter and CC using clinical cervical samples. Pyrosequencing was performed to detect the methylation status of the SOX21-AS1 promoter in 33 cervical specimens. Additionally, expression levels of related genes in 43 clinical cervical specimens were measured using quantitative real-time PCR (qRT-PCR). The SOX21-AS1 promoter was significantly hypomethylated in CC (P < 0.01). SOX21-AS1 hypomethylation was also significantly associated with an advanced Federation of Gynecology and Obstetrics (FIGO) stage (P < 0.01). The expression levels of SOX21-AS1 and SOX21 were noted to be higher in cancer vs. normal cervix (all P < 0.001). Moreover, the expression of SOX21-AS1 was positively correlated with SOX21 in all samples (r = 0.891, P < 0.001). Methylation statue of the SOX21-AS1 promoter region was negatively correlated with the expression levels of SOX21-AS1 and SOX21 (SOX21-AS1, r = - 0.628; SOX21, r = - 0.648; both P < 0.001). The methylation status of SOX21-AS1 displayed promising diagnostic potential for CC, exhibiting good sensitivity (100.0%) and specificity (69.2%), with an area under the curve of 0.846. In addition, bioinformatic analyses identified a potential link between SOX21-AS1 and the Wnt signaling pathway. Furthermore, methylation status of SOX21-AS1 was negatively correlated with β-catenin/c-myc/cyclin D1 mRNA levels (r

LncRNA HOXA-AS2 Activates the Notch Pathway to Promote Cervical Cancer Cell Proliferation and Migration

Long non-coding RNAs (lncRNAs) are crucial participants in cancer development. HOXA cluster antisense RNA 2 (HOXA-AS2) plays a tumor promoter role in bladder cancer. However, the functional role of HOXA-AS2 in cervical cancer remains unclear. Our study first found that HOXA-AS2 expression was up-regulated in cervical cancer cells. Then functional analysis including cell counting kit-8 (CCK-8), colony formation, transwell, and wound healing uncovered that reduction of HOXA-AS2 remarkably impeded cell proliferation and migration in cervical cancer. Additionally, luciferase reporter assays were performed to confirm that HOXA-AS2 activated Notch signaling pathway via the mediation of independent recombination signal binding protein for JK (RBP-JK) activity. As we know, Notch intracellular domain (NICD) is associated with RBP-JK in the nucleus to promote target genes in the Notch pathway. Through RNA immunoprecipitation (RIP), RNA pull down, and fluorescent in situ hybridization (FISH) assays, we observed that HOXA-AS2 combined with NICD. Moreover, the data from Co-IP assays indicated that HOXA-AS2 reduction weakened the interaction of NICD and RBP-JK. Collectively, HOXA-AS2 played a cancer-promoting role in cervical cancer development by modulating the Notch pathway, which might become a novel target for cervical cancer treatment.

Circ_0019435 Exerts Its Functions in the Cellular Process of Cervical Cancer via Epigenetically Silencing DKK1 and PTEN

Cervical cancer (CC) is the most serious gynecological malignancy among women worldwide. As a subtype of noncoding RNAs (ncRNAs), circular RNAs (circRNAs) play important roles in the regulation of gene expression and cancer progression. It was discovered from the cancer-specific circRNA database (CSCD) that circ_0019435 was mainly distributed in the nucleus of HeLa-S3 cells. However, few researches have mentioned circ_0019435 with its function in cancers. The present study uncovered that circ_0019435 was upregulated in CC cells by qRT-PCR. Moreover, circ_0019435 was more stable than its linear isoform-ABCC2. Besides, no regulation of circ_0019435 on ABCC2 and the chemoresistance of CC cells were found. Then, it was unveiled by a series of functional assays including colony formation, trypan blue staining, and transwell invasion assays in that circ_0019435 ablation induced the suppression of proliferation, invasion, and EMT of HeLa and SiHa cells. The subcellular distribution of circ_0019435 was assessed by subcellular fractionation and FISH assay. Furthermore, it was disclosed that circ_0019435 binds to EZH2 to silence DKK1 and PTEN. Finally, rescue assays corroborated that DKK1 and PTEN were involved in circ_0019435-mediated CC cell progression. In conclusion, circ_0019435 regulates DKK1 and PTEN expression at the epigenetic level, thereby influencing the progression of CC cells.

MiR-106b-5p Promotes Malignant Behaviors of Cervical Squamous Cell Carcinoma Cells by Targeting TIMP2

The objective of this study was to investigate modulatory mechanism of miR-106b-5p and tissue inhibitor of metalloproteinases 2 (TIMP2) on cervical squamous cell carcinoma cells. Differentially expressed genes in CSCC were analyzed via bioinformatics analysis. The targeting impact of miR-106b-5p on TIMP2 was validated through dual-luciferase assay and RNA immunoprecipitation assay. MiR-106b-5p level and TIMP2 mRNA level were assessed via qRT-PCR. TIMP2 protein level was measured via western blot. Malignant behaviors of CSCC cells were evaluated by functional experiments. The EMT and apoptosis-related proteins were determined via western blot. MiR-106b-5p was noticeably elevated in CSCC cells. Its downstream target was TIMP2. MiR-106b-5p and TIMP2 levels were inversely correlated. MiR-106b-5p overexpression fostered malignant phenotypes of CSCC cells, and vice versus. TIMP2 overexpression weakened the promotive impact of forced expression of miR-106b-5p on CSCC cell growth. EMT was facilitated by forced expression of miR-106b-5p. MiR-106b-5p regulates the progression of CSCC cells via targeting TIMP2, which may provide novel value for development of therapeutic targets for CSCC.

Monogram and Heat Map on Magnetic Resonance Imaging to Evaluate the Recommendation for Myomectomy in Patients with Infertility: A Pilot Study

Uterine myomas can cause infertility. Studies are attempting to determine the indications for myomectomy. However, the multiplicity and localization of myomas complicate this issue. We aimed to develop a visualization tool to aid patients with infertility in their decision-making for myomectomy. We included 191 women with uterine myoma attending an outpatient infertility clinic, of whom 124 patients underwent myomectomy. Of these, 65 (52.4%) patients became pregnant within 17.6 months after surgery, and 54 (83.1%) of them had a live birth. A logistic regression model predicting the pregnancy rate (area under the curve, 0.82; 95% confidence interval, 0.74-0.89; validation value, 74.6%) was generated using the leave-one-out cross-validation method. This model incorporated five factors: age, maximum level of infertility intervention following myomectomy, presence of submucosal myoma, maximum diameter of the myoma, and type of myomas (multiple or single). We successfully visualized the degree of involvement of each factor in the pregnancy rate by developing a nomogram based on this model. We expanded the data from the preoperative magnetic resonance images and applied machine learning using a convolutional neural network. The classification accuracy was 71.4% for sensitivity and 77.7% for specificity. Heatmap images, generated using gradient-weighted class activation mapping to show the classification results of this model, could distinguish between myomas that required enucleation and those that did not. Although a larger sample size is needed to further validate our findings, this innovative pilot study demonstrates the potential of machine learning to refine assessment criteria and improve patient decision-making.

CircRNA circ-ATAD1 Is Upregulated in Cervical Squamous Cell Carcinoma and Regulates Cell Proliferation and Apoptosis by Suppressing the Maturation of miR-218

The oncogenic function of circ-ATAD1 has been characterized in gastric cancer, while its role in cervical squamous cell carcinoma (CSCC) is unclear. This study explored the role of circ-ATAD1 in CSCC. To evaluate the differential expression of circ-ATAD1, mature miR-218, and premature miR-218 in CSCC, a total of 62 CSCC patients were subjected to biopsies to collect CSCC and paired normal tissues. Gene expression levels were quantified by RT-qPCRs. Nuclear fractionation assay was performed to analyze the subcellular location of circ-ATAD1. CSCC cells were used to perform cell transfections to explore the crosstalk between circ-ATAD1 and miR-218. The roles of circ-ATAD1 and miR-218 in CSCC cell behaviors were explored by BrdU assay, Transwell assay, cell apoptosis assay, and cell stemness assay. CSCC tissues exhibited upregulated expression of circ-ATAD1, which was localized to both nucleus and cytoplasm. Mature miR-218 was downregulated in CSCC tissues and was inversely correlated with circ-ATAD1, while premature miR-218 was not differentially expressed in CSCC. Upregulation of circ-ATAD1 in CSCC cells decreased the expression levels of mature miR-218, but not that of premature miR-218. In addition, overexpression of circ-ATAD1 increased cell proliferation and decreased cell apoptosis, while overexpression of miR-218 decreased cell proliferation and increased cell apoptosis, and it also attenuated the effects of overexpression of circ-ATAD1 on cell proliferation. However, CSCC cell invasion, migration, and stemness were not affected by circ-ATAD1 and miR-218. Circ-ATAD1 is upregulated in CSCC and may regulate cell proliferation and apoptosis by suppressing the maturation of miR-218.

BMAL1 Regulates Collagen Production in the Myometrium and Leiomyomas

Infertility and reproductive issues are commonly observed in animals with clock abnormalities. Substantial rodent data is available; however, relatively few studies have investigated the connection between fertility and clock abnormalities in humans. Therefore, this study aimed to analyze the expression of circadian clock genes and their impact on genes involved in collagen production in the human myometrium and leiomyomas (LM). The relationship between the expression of brain and muscle aryl-hydrocarbon-receptor-nuclear-translocator (Arnt)-like protein-1 (BMAL1) and the genes responsible for collagen synthesis in the human MM and LMs were investigated. Human MM and LM tissues were collected for analysis from patients who underwent hysterectomy analysis. Immunohistochemical analysis, cell culturing, immunofluorescence, small interfering RNA transfection, reverse transcription quantitative real-time polymerase chain reaction, scratch wound assays, and transwell assays were employed to gain a comprehensive understanding of the cellular and molecular processes. A correlation was found between BMAL1 expression and genes regulating collagen synthesis in primary cultures of human MM and LM cells. Moreover, the inhibition of BMAL1 differentially increased the migration and invasion of MM and LM cells. This work discloses the role of BMAL1 in collagen production in primary cultures of human MM and LM cells, offering insight into clock gene involvement in both normal and pathological uterine conditions. Furthermore, this study highlights the crucial role of BMAL1 in collagen synthesis in human MM and LM cells, underscoring the significance of BMAL1 in the regulation of reproductive physiology. These results suggest that BMAL1 might be a useful target molecule for anti-LM therapy.

Elucidation of Increased Cervical Cancer Risk Due to Polymorphisms in XRCC1 (R399Q and R194W), ERCC5 (D1104H), and NQO1 (P187S)

Genetic variations like single nucleotide polymorphisms (SNPs) are associated with cervical carcinogenesis. In this study, SNPs have been identified that contribute toward changes in the function and stability of the proteins and show association with cervical cancer. Initially, literature mining identified 114 protein-coding polymorphisms with population-based evidence in cervical cancer. Subsequently, the functional assessment was performed using sequence-dependent tools, and thereafter, protein stability was analyzed using sequence and structural data. Twenty-three non-synonymous SNPs (nsSNPs) found to be damaging and destabilizing were then analyzed to check their risk association at the population level. The meta-analysis indicated that polymorphisms in DNA damage repair genes XRCC1 (rs25487 and rs1799782), ERCC5 (rs17655), and oxidative stress-related gene NQO1 (rs1800566) are significantly associated with increased cervical cancer risk. The XRCC1 rs25487 and rs1799782 polymorphisms showed the highest risk of cervical cancer in the homozygous model having odds ratio (OR) = 1.85, 95% confidence interval (CI) = 1.17-2.92, p = 0.01, and recessive model with OR = 1.81, 95% CI = 1.01-3.24, and p = 0.04 respectively. Similarly, rs17655 polymorphism of ERCC5 and rs1800566 polymorphism of NQO1 showed the highest pooled OR in the homozygous (OR = 1.70, 95% CI = 1.32-2.19, p = 0.00004) and heterozygous model (OR = 1.3, 95% CI = 1.06-1.58, p = 0.01) respectively. Thus, in this study, a comprehensive collection of nsSNPs was collated and assessed, leading to the identification of polymorphisms in DNA damage repair and oxidative stress-related genes, that destabilize the protein and shows increased risk associated with cervical cancer.

Landscape and Construction of a Novel N6-methyladenosine-related LncRNAs in Cervical Cancer

Cervical cancer is a crucial clinical problem with high mortality. Despite much research in therapy, the prognosis of patients with cervical cancer is still not ideal. The data on cervical cancer were downloaded from The Cancer Genome Atlas (TCGA) portal. R language was used to screen out the N6-methyladenosine (m6A)-related lncRNAs (long non-coding RNA). A consensus clustering algorithm was performed to identify m6A-related lncRNAs in cervical cancer; 10 m6A-related lncRNAs showing a significant association with survival were filtrated through a gradually univariate Cox regression model, least absolute shrinkage and selection operator (LASSO) algorithm, and multivariate Cox regression preliminarily. Furthermore, we conducted Kaplan-Meier curves, receiver operating curve (ROC) analyses, and proportional hazards model to quantify the underlying character of the m6A-related model in the prevision of cervical cancer patients. Gene set enrichment analysis (GSEA) was used to explore several pathways significantly. Finally, cell-type identification by estimating relative subsets of RNA transcripts (CIBERSORT) was applied to estimate the immune cell infiltration in the profiling. In the present study, 10 m6A-related lncRNAs make up our prediction model. This prediction model can do duty for an independent predictive biomolecular element. Subsequently, we then found that the model was still valid in further validation of the training group and the test group. Our signature was correlated with immune cell infiltration and partial signaling pathway. These lncRNAs played a no negligible biomolecular role in contributing to the prognosis of cervical cancer.

Circ_0042986 Presence Restrains Cervical Cancer Development via Upregulating PEG3 by Directly Targeting miR-582-3p

The participation of circular RNAs (circRNAs) in carcinogenesis is widely established. Numerous circRNAs with aberrant expression in cervical cancer (CC) are identified by RNA sequencing, whereas the function of these circRNAs remains unclear. We thus aimed to unveil the effects and mechanisms of circ_0042986 in CC. Circ_0042986 with aberrant downregulation in CC was obtained from GSE10286 dataset. qPCR and western blotting were employed for the detection of circ_0042986, miR-582-3p, and paternally expressed 3 (PEG3) expressions. EdU assay, colony formation assay, wound healing assay, transwell assay, tube formation assay, and flow cytometry assay were applied for functional analyses. The potential binding site was ensured by dual-luciferase reporter analysis, and their binding relationship was verified by pull-down assay. The transplanted tumor models were constructed for in vivo function verification of circ_0042986. Our findings exposed that the downregulation of circ_0042986 was verified in clinical CC samples. Circ_0042986 overexpression largely attenuated CC cell growth, invasiveness, angiogenesis, and survival. MiR-582-3p was targeted by circ_0042986, and the inhibitory roles of circ_0042986 presence were partly abolished by miR-582-3p enrichment. MiR-582-3p combined with PEG3, and circ_0042986 increased PEG3 expression via decoying miR-582-3p. The interaction between miR-582-3p and PEG3 on CC cell functions was confirmed, evidenced by the reversal effects of PEG3 knockdown on miR-582-3p deficiency-inhibited cancer cell malignant behaviors. Circ_0042986 overexpression also limited tumorigenesis of CC in animal models. In summary, circ_0042986 overexpression decoyed miR-582-3p to increase PEG3 expression, thereby blocking the malignant progression of CC.

Circ_0000263 facilitates the proliferation and inhibits the apoptosis of cervical cancer depending on the regulation of miR-1179/ABL2 axis

Circular RNA (circRNA) has been reported to participate in the progression of cervical cancer (CC). Studies on the role and mechanism of circ_0000263 in CC are limited, and more studies are needed. The expression of circ_0000263, microRNA (miR)-1179 and ABL proto-oncogene 2 (ABL2) mRNA in tissues and cells was analyzed by quantitative real-time PCR. The proliferation and apoptosis of CC cells were determined using cell counting kit 8 assay, Edu assay, colony formation assay and flow cytometry. The protein expression of proliferation markers, apoptosis markers and ABL2 was detected by western blot analysis. The interaction between RNAs was estimated via dual-luciferase reporter assay. Xenograft models were applied to explore the effect of circ_0000263 knockdown on CC tumorigenesis. Circ_0000263 was highly expressed in CC tumor tissues. Silencing of circ_0000263 suppressed CC cell proliferation and increased apoptosis. Circ_0000263 served as a sponge for miR-1179, and miR-1179 inhibitor reversed the regulation of si-circ_0000263 on CC cell proliferation and apoptosis. ABL2 could be targeted by miR-1179, and circ_0000263 could sponge miR-1179 to regulate ABL2. Overexpression of ABL2 reversed the anti-proliferation and pro-apoptosis roles of miR-1179 in CC cells. In addition, circ_0000263 knockdown reduced CC tumor growth by miR-1179/ABL2 axis. In brief, the results demonstrated that circ_0000263 exerted an oncogene role in CC, which suggested that circ_0000263 might be a promising therapeutic target for CC.

Long Non-coding RNA UCA1a Promotes Proliferation via PKM2 in Cervical Cancer

Cervical cancer is a common malignancy that affects women worldwide. The long non-coding RNA (lncRNA) urothelial cancer-associated 1a (UCA1a) is reported to be significantly upregulated in cervical cancer. However, the exact role of UCA1a in cervical cancer remains unknown. This study aimed to identify two core promoter regions in UCA1a, which are essential for CEBPA-dependent transcription and FOXL1-, FOXL4-, and FOXL6-dependent activation, respectively. RNA sequencing results showed that overexpression of UCA1a resulted in extensive changes in the gene expression profile of HeLa cells, especially in the signaling pathway that regulates tumorgenesis. Mass spectrometry assay was conducted to show that pyruvate kinase M2 (PKM2) was a UCA1a-interacting protein. The 400 ~ 800 nt long region of UCA1a at the 5' end and the A1B domain of PKM2 were critical for the UCA1a-PKM2 interaction. Functional assays were performed to show that PKM2 was sufficient and necessary for UCA1a-induced proliferation of HeLa cells, which was partly due to the regulating of nuclear translocation and stabilization of PKM2. These findings provide a novel mechanism for UCA1a to regulate Hela cells by ubiquitination degradation of PKM2 and suggest that UCA1a may play a key role in the progression of cervical cancer.

E2F Transcription Factor 1 Activates FKBP Prolyl Isomerase 4 to Promote Angiogenesis in Cervical Squamous Cell Carcinoma Via the PI3K/AKT Signaling Pathway

Angiogenesis, namely the formation of blood vessels, is crucial for tumor growth, metastasis and development. E2F transcription factor 1 (E2F1) has been linked to tumorigenesis in several human cancers. This work examines the role of E2F1 and its downstream targets in angiogenesis in cervical squamous cell carcinoma (CSCC). E2F1 was predicted as a candidate oncogene in CSCC using a GSE63514 dataset. Increased E2F1 expression was detected in CSCC tumor samples and cell lines by RT-qPCR, immunohistochemistry, and western blot assays. E2F1 downregulation reduced the angiogenesis activity of HUVECs and the invasiveness of CSCC cells. In vivo, E2F1 knockdown also reduced the xenograft tumor growth and promoted tumor necrosis in mice. FKBP prolyl isomerase 4 (FKBP4) was identified as a target of E2F1. E2F1 bound to FKBP4 promoter for transcriptional activation. Further upregulation of FKBP4 blocked the tumor-suppressive role of E2F1 silencing. FKBP4 was enriched in the PI3K/AKT signaling. In cells and xenograft tumors, the E2F1/FKBP4 axis promoted PI3K and AKT phosphorylation. Activation of the PI3K/AKT signaling restored the angiogenesis activity in cells blocked by E2F1 silencing. In summary, this work demonstrates that E2F1 promotes FKBP4 transcription to activate the PI3K/AKT pathway, which augments the angiogenesis and invasiveness of CSCC.

CircRNA VPRBP inhibits tumorigenicity of cervical cancer via miR-93-5p/FRMD6 axis

Cervical cancer is a malignant tumor that threatens the life and health of women. Circular RNA (circRNA) is a research hotspot in human diseases including cervical cancer. However, the research of circRNA viral protein R-binding protein (circ_VPRBP) in cervical cancer is blank. Real-time quantitative polymerase chain reaction (RT-qPCR) was used to detect the expression of target genes in cervical cancer tissues and cells. The expression of related proteins was detected by western blot. The localization of circ_VPRBP was detected by nuclear cytoplasmic separation, and the stability of circ_VPRBP was verified by actinomycin D. After transfection with oligonucleotides and/or plasmids, cell proliferation, migration, invasion and apoptosis were detected by 3-(4, 5-dimethylthiazol-2-yl) -2, 5-diphenyl-2-H-tetrazolium bromide (MTT), colony formation, 5-ethynyl-2'-deoxyuridine (EdU), transwell, or flow cytometry assays. Mechanistically, the interaction between microRNA-93-5p (miR-93-5p) and circ_VPRBP/FERM domain containing 6 (FRMD6) was verified by dual luciferase reporter assay. Animal experiment was conducted to investigate the role of circ_VPRBP in vivo. Circ_VPRBP was down-regulated in cervical cancer tissues and cells, and overexpression of circ_VPRBP inhibited proliferation and promoted apoptosis of Caski and C33A cells. MiR-93-5p was a target of circ_VPRBP, and miR-93-5p mimic reversed the effect of circ_VPRBP on cell behavior. FRMD6 was a downstream target of miR-93-5p, and down-regulated FRMD6 reversed the cell viability, migration and invasion of cervical cancer cells inhibited by anti-miR-93-5p. Circ_VPRBP inhibited tumor growth by regulating miR-93-5p and FRMD6 in vivo. Circ_VPRBP inhibited cell proliferation, migration and invasion and promoted cell apoptosis of cervical cancer cells by regulating miR-93-5p/FRMD6 axis.

Research Progress in the Relationship Between P2X7R and Cervical Cancer

Cervical cancer is one of the most common and serious tumors in women. Finding new biomarkers and therapeutic targets plays an important role in the diagnosis, prognosis, and treatment of cervical cancer. Purinergic ligand-gated ion channel 7 receptor (P2X7R) is a purine ligand cation channel, activated by adenosine triphosphate (ATP). Studies have shown that P2X7R plays an important role in a variety of diseases and cancers. More and more studies have shown that P2X7R is also closely related to cervical cancer; therefore, the role of P2X7R in the development of cervical cancer deserves further discussion. The expression level of P2X7R in uterine epithelial cancer tissues was lower than that of the corresponding normal tissues. P2X7R plays an important role in the apoptotic process of cervical cancer through various mechanisms of action, and both antagonists and agonists of P2X7R can inhibit the proliferation of cervical cancer cells, while P2X7R is involved in the antitumor effect of Atr-I on cervical cancer cells. This review evaluates the current role of P2X7R in cervical cancer in order to develop more specific therapies for cervical cancer. In conclusion, P2X7R may become a biomarker for cervical cancer screening, and even a new target for clinical treatment of cervical cancer.

Exosome-Mediated Transfer of miR-1323 from Cancer-Associated Fibroblasts Confers Radioresistance of C33A Cells by Targeting PABPN1 and Activating Wnt/β-Catenin Signaling Pathway in Cervical Cancer

Plenty of pieces of evidence suggest that the resistance to radiotherapy greatly influences the therapeutic effect in cervical cancer (CCa). MicroRNAs (miRNAs) have been reported to regulate cellular processes by acting as tumor suppressors or promoters, thereby driving radioresistance or radiosensitivity. Meanwhile, it has been reported that microRNA-1323 (miR-1323) widely participates in cancer progression and radiotherapy effects. However, the role of miR-1323 is still not clear in CCa. Hence, in this study, we are going to investigate the molecular mechanism of miR-1323 in CCa cells. In the beginning, miR-1323 was found aberrantly upregulated in CCa cells via RT-qPCR assay. Functional assays indicated that miR-1323 was transferred by cancer-associated fibroblasts-secreted (CAFs-secreted) exosomes and miR-1323 downregulation suppressed cell proliferation, migration, invasion, and increased cell radiosensitivity in CCa. Mechanism assays demonstrated that miR-1323 targeted poly(A)-binding protein nuclear 1 (PABPN1). Besides, PABPN1 recruited insulin-like growth factor 2 mRNA binding protein 1 (IGF2BP1) to regulate glycogen synthase kinase 3 beta (GSK-3β) and influenced Wnt/β-catenin signaling pathway. Therefore, rescue experiments were implemented to validate that PABPN1 overexpression rescued the inhibited cancer development and radioresistance induced by the miR-1323 inhibitor. In conclusion, miR-1323 was involved in CCa progression and radioresistance which might provide a novel insight for CCa treatment.

LOC100130075 Promotes Cervical Cancer Progression by Activating MDM2 Transcription through E2F1

Cervical cancer (CC) represents one of the most frequent gynecological tumors worldwide and it takes a big part in cancer-related deaths in women. The mouse double minute 2 (MDM2) gene has been elucidated to be deregulated in cancers and exert its oncogenic activity. Through ENCODE ( https://www.encodeproject.org/ ), LOC100130075 was discovered to be a nearby gene of MDM2. Emerged as a novel long non-coding RNA (lncRNA), LOC100130075 has not been studied in cancers. Therefore, we aim to figure out the function of LOC100130075 and its interaction with MDM2 in CC progression. The high expression pattern of LOC100130075 and MDM2 and a positive correlation between them were firstly verified in CC cells. Then, it was verified that LOC100130075 interference suppressed the proliferation and enhanced the apoptosis of CC cells. Furthermore, we verified through mechanism assays including ChIP, RNA pull-down, as well as luciferase reporter assays that LOC100130075 bound to E2F transcription factor 1 (E2F1) to activate MDM2 transcription. Furthermore, the result of rescue assays manifested that MDM2 overexpression reversed the inhibitory function of LOC100130075 deficiency on CC development. In a word, LOC100130075 promoted CC malignancy by activating MDM2 transcription through E2F1, which may provide a new direction in the advancement of CC treatments.

Hsa_circ_0074269-mediated Upregulation of TUFT1 Through miR-485-5p Increases Cisplatin Resistance in Cervical Cancer

Most cervical cancer patients are prone to developing acquired cisplatin (DDP) resistance. Hsa_circ_0074269 (circ_0074269) plays a promoting role in cervical cancer, but whether circ_0074269 mediates cervical cancer resistance to DDP is unclear. Expression of circ_0074269 was detected by real-time quantitative polymerase chain reaction (RT-qPCR). The half-maximal inhibitory concentration (IC

The Feasibility of Large Conization as a Fertility-Sparing Treatment in Young Women with Early-Stage Cervical Cancer

Among the cancers affecting women of all age groups, cervical cancer (CCa) is fourth most prevalent globally. Improved screening programs have aided the early detection of cervical cancer in young women seeking fertility. In this issue of Reproductive Sciences, Tsaousidis et al. retrospectively analyzed the use of large conization (LC) in 23 patients with early-stage CCa (9 stage IA and 14 stage IB). The authors chose 4 different domains to report outcomes of interest: surgical, oncological, fertility, and obstetric. Overall, the authors reported good outcomes after LC with a median follow-up of 58 months. We briefly reviewed the literature for similar studies reporting on fertility-preserving treatments for CCa. In addition, a brief note on the possible role of neoadjuvant chemotherapy was added. Future research on fertility-preserving treatment must accurately report inclusion criteria to better delineate the indications for it: good surgical outcomes require good patient selection.

Circ_0003221 Downregulation Restrains Cervical Cancer Cell Growth, Metastasis and Angiogenesis by Governing the miR-139-3p/S100A14 Pathway

Circular RNA (circRNA) has considerable potency in carcinogenesis, which has aroused much attention. The objective of our study was to disclose the role of circ_0003221 in cervical cancer. Circ_0003221, miR-139-3p, and S100 calcium-binding protein A14 (S100A14) mRNA were quantified by quantitative real-time PCR (qPCR). The proliferation of cancer cells was checked by CCK-8 assay and EdU assay. The migration and invasion of cancer cells were checked by transwell assay. Angiogenesis was determined by tube formation assay. The protein levels of epithelial-mesenchymal transition (EMT)-related markers, angiogenesis-related markers, and S100A14 protein were measured by western blot. The interplays between miR-139-3p and circ_0003221 or S100A14 were ensured by RIP assay and dual-luciferase reporter assay. Further animal study was conducted to verify the role of circ_0003221 in vivo. Circ_0003221 was highly expressed in cancer tissues and cells, and its downregulation suppressed cancer cell proliferation, migration, invasion, and angiogenesis and also delayed tumor growth in vivo. Circ_0003221 bound to miR-139-3p and sequestered miR-139-3p expression. The inhibitory cancer cell biological behaviors by circ_0003221 downregulation were recovered by miR-139-3p suppression. S100A14 was a target gene of miR-139-3p. MiR-139-3p upregulation repressed cancer cell malignant phenotypes by depleting S100A14. Importantly, circ_0003221 positively regulated S100A14 expression by targeting miR-139-3p. Circ_0003221 downregulation restrains cervical cancer cell growth, metastasis, and angiogenesis by governing the miR-139-3p/S100A14 pathway.

The Solute Carrier (SLC) Transporter Superfamily as Therapeutic Targets for the Treatment of Ovarian Serous Cystadenocarcinoma

Challenges in Fertility Preservation for p53abn Grade 2 Endometrioid Endometrial Cancer: A Case Report and Literature Review

Endometrial carcinoma, the second most common gynecological cancer, is increasingly affecting younger women, particularly due to rising obesity rates. The need for precise molecular tools is paramount for better categorization and risk stratification, especially in fertility preservation, as current methods often fall short. Fertility preservation is considered for early-stage, nonmetastatic cases, but the role of molecular classifications in this area remains underexplored. We present the case of a 35-year-old woman with grade 2 p53abn endometrioid endometrial cancer who sought fertility preservation. Her initial treatment involved hysteroscopy-guided resection, hormonal therapy with megestrol acetate (MA), and close monitoring, but the disease recurred within six months. A literature review reveals that fertility preservation in p53abn endometrial carcinoma is poorly documented, with variable outcomes. Many cases indicate a poor response to progestin therapy and a heightened risk of recurrence, highlighting the need for personalized treatment approaches. Additionally, our case identifies "a novel PTEN somatic mutation (Tier 2C)" that has not been previously reported in endometrial cancer. This case underscores the essential role of molecular profiling in clinical decision-making and the need for ongoing research into molecular pathways. Integrating molecular classifiers into routine practice is crucial for improving risk stratification and treatment outcomes, especially in young women pursuing fertility preservation.

HERC2 as a Potential Biomarker for Prognosis and Response to Bevacizumab in Ovarian Cancer: A Bioinformatics Approach

It is thought that decreased HERC2 expression increases the sensitivity to ferroptosis in ovarian cancer cells and may increase the VEGF pathway in porcine endothelium by inhibiting LKB1. Based on these data, we aimed to determine whether HERC2 expression may have a positive prognostic significance in patients receiving anti-VEGF based therapy in ovarian cancer patients. The study used public databases and has a retrospective design. Following web tools or datasets were used: TCGA TARGET GTEX study (n = 427 cancer vs. 88 normal ovarian tissue) at UCSC Xena and CPTAC at UALCAN for expression, Kaplan-Meier plotter for overall survival (OS) (n = 1207 for serous histology and n = 37 for endometrioid histology in gene chip), progression-free survival (PFS) (n = 1104 for serous histology in gene chip), TIMER2.0 for correlation of PDCD1, CTLA4, CD274 (PDL1), GEPIA2 for immune gene signatures, OncoLnc, DoSurvive and OncomiR for miRNA and OS associations, CancerSEA for functional status analyses. HERC2 expression levels were lower in ovarian serous cystadenocarcinoma (OV). Lower HERC2 expression was also seen in CPTAC ovarian cancer cohort. In the overall ovarian cancer cohort, decreased HERC2 expression was associated with longer OS. In the serous histology cohort, decreased HERC2 expression was associated with shorter PFS in those receiving bevacizumab-containing chemotherapy. PDL1 and HERC2 expressions were positively correlated. hsa-miR-500a-3p was negatively correlated with HERC2 in OV, and increased expression of this miRNA was associated with better OS. There was a positive association between HERC2 expression and angiogenesis and EMT, and a negative association with invasion. Decreased HERC2 expression is associated with a favorable prognosis in overall ovarian cancer cohort, but is associated with a worse PFS in patients receiving bevacizumab with serous ovarian cancer.

Long Non-Coding, Micro, and Circular RNAs in Ovarian Cancer Metastasis: Pathways and Treatment Approaches

Gynaecologic cancer is a major cause of death for women and the most well-known ovarian cancer (OC) has a high mortality rate. Given that the majority of ovarian cancer deaths are caused by metastatic tumors that have spread to nearby tissues, several biological processes, including angiogenesis and metastasis, have a role in the onset and course of these diseases. Numerous non-coding RNAs (ncRNAs) have been shown in recent studies to contribute to the invasion and metastasis of ovarian cancer by altering particular cellular pathways. Three forms of ncRNAs which are long non-coding RNAs, micro RNAs, and circular RNAs are the subjects of this review. miRNA is used as a potential biomarker such as miR-375 which is a serum exosome and also in therapeutics. lncRNA sponges with miRNA which sequesters and regulates tumor progression such as XIST miR-149-3p. circRNA targets proteins and regulates gene expression. This review provides an overview of the precise function of non-coding RNAs in the many pathways and molecular exchanges that contribute to the invasion and metastasis of malignancies. To increase the survival rate of OC patients, new approaches to ncRNA-targeted therapy are being utilised, including targeting lncRNAs and circRNAs and modulating the tumor microenvironment using exosomes.

Effects of Thyroid Hormones on Cellular Development in Human Ovarian Granulosa Tumor Cells (KGN)

Ovarian cancer is a common malignant tumor in the female reproductive system, and Granulosa cell tumor (GCT) of the ovary is a rare type of ovarian cancer, which significantly threatens women's reproductive health. It has been reported that dysregulation of thyroid hormones (THs) may be closely related to the progression and prognosis of ovarian cancer. Moreover, THs regulate phosphorylation of signal transducer and activator of transcription (STAT3) and Octamer-binding transcription factor 4 (OCT4) expression. It has been reported that STAT3 and OCT4 play important roles in cellular development and tumorigenesis. However, the mechanisms by which THs affect the development of GCT are still remained unclear. To evaluate the effect of THs on human ovarian granulosa tumor cells (KGN), cells were treated with 3,5,3' -triiodothyronine (T

Amphiregulin Downregulates E-cadherin Expression by Activating YAP/Egr-1/Slug Signaling in SKOV3 Human Ovarian Cancer Cells

Amphiregulin (AREG) stimulates human epithelial ovarian cancer (EOC) cell invasion by downregulating E-cadherin expression. YAP is a transcriptional cofactor that has been shown to regulate tumorigenesis. This study aimed to examine whether AREG activates YAP in EOC cells and explore the roles of YAP in AREG-induced downregulation of E-cadherin and cell invasion. Analysis of the Cancer Genome Atlas (TCGA) showed that upregulation of AREG and EGFR were associated with poor survival in human EOC. Treatment of SKOV3 human EOC cells with AREG induced the activation of YAP. In addition, AREG downregulated E-cadherin, upregulated Egr-1 and Slug, and stimulated cell invasion. Using gain- and loss-of-function approaches, we showed that YAP was required for the AREG-upregulated Egr-1 and Slug expression. Furthermore, YAP was also involved in AREG-induced downregulation of E-cadherin and cell invasion. This study provides evidence that AREG stimulates human EOC cell invasion by downregulating E-cadherin expression through the YAP/Egr-1/Slug signaling.

BRCA1/2 Mutations and Breast/Ovarian Cancer Risk: A New Insights Review

Breast and ovarian cancers are significant global health concerns, and understanding their genetic underpinnings is essential for effective prevention and cure. This narrative review provides a comprehensive analysis of studies conducted between 1994 and June 2024, focusing on the link between specific mutations in the breast cancer susceptibility gene 1 (BRCA1) and breast cancer susceptibility gene 2 (BRCA2) and the associated risks of both breast and ovarian cancers. It encompasses the findings of various works, including observational studies and molecular profiling analyses. Conducted on large international cohorts, these studies present compelling evidence of the relationship between different BRCA1 and BRCA2 mutations and the varying risks of breast and ovarian cancer. Furthermore, this review highlights the significance of nonsense-mediated decay mutations and their impact on cancer risk, particularly concerning the age of breast cancer onset. The implications of these findings are far-reaching, offering valuable information for risk assessment and decision-making in managing individuals who carry BRCA1 or BRCA2 mutations. The molecular subtyping profile BluePrint is discussed as a potential tool for enhancing clinical care by aiding the selection of appropriate treatment options, such as endocrine therapy or chemotherapy, based on the tumor's molecular characteristics. In conclusion, we establish a robust link between specific BRCA1 and BRCA2 gene mutations and increased susceptibility to breast and ovarian cancers. These mutations impact cancer onset age and severity, underscoring the need for targeted testing and screening. The current study enhances cancer detection, prevention, and cure strategies.

Ultrasonography Findings in Ovarian Hemangiomas: Report of Three Cases and Review of the Literature

Ovarian hemangioma is a rare ovarian tumor. The imaging manifestations were rarely mentioned in previous literatures. One of the patients came to hospital with the complaints of an elevation of CA125. Another two patients found a mass in adnexa area accidentally. The oophorectomy procedures were performed and the pathological results of ovarian hemangioma were concluded. We summarized the ultrasound features of three cases retrospectively, of which could provide more information before operation to guide a management direction. A well-defined, regular-shape solid mass in ovary could be considered the possibility of hemangioma, especially when a richly vascularized tumor with prominent blood flow is detected on color Doppler sonography.

The Promise and Challenges of AI Integration in Ovarian Cancer Screenings

Ovarian cancer is oftendiagnosed late due to vague symptoms, leading to poor survival rate. Improved screening tests could mitigate this issue. This narrative review examines the potential and challenges of integrating artificial intelligence (A.I.) into ovarian cancer screenings, with a focus on improving early detection, diagnosis, and personalized risk assessment. A comprehensive review of existing literature was conducted, analyzing studies and discussions within the scientific community. A.I. shows promise in significantly improving the ovarian cancer screening processes, increasing accuracy, efficiency, and resource allocation. However, data quality and bias issues pose considerable challenges, potentially leading to healthcare disparities. Integrating A.I. into ovarian cancer screenings offers potential benefits but comes with significant challenges. By promoting diverse data collection, engaging with underrepresented groups, and ensuring ethical data use, A.I. can be harnessed for more accurate and equitable ovarian cancer diagnoses.

Granulosa Cells-Related MicroRNAs in Ovarian Diseases: Mechanism, Facts and Perspectives

MicroRNAs (miRNAs) are a class of short single-stranded, noncoding RNAs that affect the translation of mRNAs by imperfectly binding to homologous 3'UTRs. Research on miRNAs in ovarian diseases is constantly expanding because miRNAs are powerful regulators of gene expression and cellular processes and are promising biomarkers. miRNA mimics, miRNA inhibitors and molecules targeting miRNAs (antimiRs) have shown promise as novel therapeutic agents in preclinical development. Granulosa cells (GCs) are supporting cells for developing oocytes in the ovary. GCs regulate female reproductive health by producing sex hormones and LH receptors. Increasing research has reported the relevance of miRNAs in GC pathophysiology. With in-depth studies of disease mechanisms, there are an increasing number of studies on the biomolecular pathways of miRNAs in gynecology and endocrinology. In the present review, we summarize the different functions of GC-related microRNAs in various ovarian disorders, such as polycystic ovary syndrome, premature ovarian insufficiency, premature ovarian failure and ovarian granulosa cell tumors.

The Multiple Functions of HB-EGF in Female Reproduction and Related Cancer: Molecular Mechanisms and Targeting Strategies

Heparin-binding growth factor (HB-EGF) is a member of the epidermal growth factor (EGF) ligand family which has a crucial role in women's health. However, there is a lack of comprehensive review to summarize the significance of HB-EGF. Therefore, this work first described the expression patterns of HB-EGF in the endometrium and ovary of different species and gestational time. Then, the focus was on exploring how it promotes the successful implantation and regulates the process of decidualization and the function of ovarian granulosa cells as an intermediate molecule. Otherwise, we also focused on the clinical and prognostic significance of HB-EGF in female-related cancers (including ovarian cancer, cervical cancer, and endometrial cancer) and breast cancer. Lastly, the article also summarizes the current drugs targeting HB-EGF in the treatment of ovarian cancer and breast cancer. Overall, these studies found that the expression of HB-EGF in the endometrium is spatiotemporal and species-specific. And it mediates the dialogue between the blastocyst and endometrium, promoting synchronous development of the blastocyst and endometrium as an intermediate molecule. HB-EGF may serve as a potentially valuable prognostic clinical indicator in tumors. And the specific inhibitor of HB-EGF (CRM197) has a certain anti-tumor ability, which can exert synergistic anti-tumor effects with conventional chemotherapy drugs. However, it also suggests that more research is needed in the future to elucidate its specific mechanisms and to accommodate clinical studies with a larger sample size to clarify its clinical value.

Pancancer Analysis of NSUN2 with a Focus on Prognostic and Immunological Roles in Endometrial Cancer

The significance of NSUN2 in carcinogenesis is gradually being recognized, yet a comprehensive analysis across pan-cancer remains a pivotal void in existing research. In our investigation, we capitalized on the UCSC Xena platform to evaluate NSUN2 expression levels and their prognostic implications across a range of cancer types. Furthermore, we employed the cBioPortal database to delve into the genomic variations of NSUN2 within human cancers. Our study encompassed the use of molecular docking, genomic tumor profiling, and an assessment of the gene's responsiveness to pharmacological treatments. Additionally, we utilized algorithmic techniques to measure the relationship between NSUN2 expression and key clinical biomarkers, such as microsatellite instability (MSI), tumor mutational burden (TMB), and immune cell infiltration. Our results have established a notable association between NSUN2 and endometrial cancer (UCEC), thereby confirming its clinical significance through an analysis of tumoral expression patterns, mutational spectra, methylation profiles, and drug sensitivity. Gene Set Enrichment Analysis (GSEA) and Gene Set Variation Analysis (GSVA) were crucial tools in elucidating the biological roles of NSUN2 in endometrial cancer. Consistently, elevated NSUN2 expression was associated with unfavorable clinical outcomes and was primarily observed in the context of genetic amplifications. Across 22 distinct tumor types, our analysis revealed a notable correlation between NSUN2 expression and various metrics related to immune cell infiltration, tumor stroma, and immune scores. Notably, higher levels of NSUN2 expression have been linked to a reduced response to certain chemotherapeutic agents, including PHA-793887. In UCEC, a positive correlation between NSUN2 methylation and gene expression hints at a potential epigenetic regulatory mechanism underlying cancer progression. Our study highlights the potential of NSUN2 as a key oncogene and its promising role as a therapeutic target as well as a prognostic biomarker for endometrial cancer. This underscores its potential importance in predicting responses to immunotherapy.

Hematological and Neurological Expressed 1 Promotes Tumor Progression Through mTOR Signaling in Ovarian Cancer

Ovarian cancer (OV) is a highly aggressive malignancy with poor prognosis due to recurrence and drug resistance. Therefore, it is imperative to investigate the key molecular mechanisms underlying OV progression in order to develop promising diagnostic and therapeutic interventions. Although the importance of hematological and neurological expressed 1 (HN1) protein in hemopoietic cell and neurological development has been well-established, its function in cancer, particularly in OV, remains uncertain. In this study, we compared the expression of HN1 in ovarian cancers and para-tumor tissues and predicted potential related signaling pathways through enrichment analysis. In order to confirm the role of HN1 in vitro and vivo, we carried out a variety of experiments including bioinformation analysis, colony formation, flow cytometry analysis, and subcutaneous tumor models. The results demonstrated that HN1 was upregulated in OV and was negatively associated with clinical prognosis. Moreover, we observed that HN1 enhances cell proliferation, migration, and drug resistance, while suppressing apoptosis in OV cells. Notably, we discovered that HN1 functions as a novel regulator of mTOR pathways. Our findings suggest that HN1-mediated mTOR regulation facilitates OV advancement and targeting HN1 could provide a promising therapeutic approach for clinical OV treatment.

Apparent Diffusion Coefficient on Diffusion-Weighted Magnetic Resonance Imaging to Predict the Prognosis of Patients with Endometrial Cancer: A Meta-Analysis

Apparent diffusion coefficient (ADC) derived from diffusion-weighted magnetic resonance imaging (DWI) may help diagnose endometrial cancer (EC). However, the association between ADC and the recurrence and survival of EC remains unknown. We performed a systematic review and meta-analysis to investigate whether pretreatment ADC on DWI could predict the prognosis of women with EC. PubMed, Embase, and Cochrane's Library were searched for relevant cohort studies comparing the clinical outcomes between women with EC having low versus high ADC on pretreatment DWI. Two authors independently conducted data collection, literature searching, and statistical analysis. Using a heterogeneity-incorporating random-effects model, we analyzed the results. In the meta-analysis, 1358 women with EC were included from eight cohort studies and followed for a median duration of 40 months. Pooled results showed that a low pretreatment ADC on DWI was associated with poor disease-free survival (DFS, hazard ratio [HR]: 3.29, 95% CI: 2.04 to 5.31, p < 0.001; I

High-Grade Endometrial Cancer: Molecular Subtypes, Current Challenges, and Treatment Options

Although many recent advancements have been made in women's health, perhaps one of the most neglected areas of research is the diagnosis and treatment of high-grade endometrial cancer (EnCa). The molecular classification of EnCa in concert with histology was a major step forward. The integration of profiling for mismatch repair deficiency and Human Epidermal Growth Factor 2 (HER2) overexpression, can further inform treatment options, especially for drug resistant recurrent disease. Recent early phase trials suggest that regardless of subtype, combination therapy with agents that have distinct mechanisms of action is a fruitful approach to the treatment of high-grade EnCa. Unfortunately, although the importance of diagnosis and treatment of high-grade EnCa is well recognized, it is understudied compared to other gynecologic and breast cancers. There remains a tremendous need to couple molecular profiling and biomarker development with promising treatment options to inform new treatment strategies with higher efficacy and safety for all who suffer from high-grade recurrent EnCa.

Establishing and Validating an Innovative Focal Adhesion-Linked Gene Signature for Enhanced Prognostic Assessment in Endometrial Cancer

Studies have highlighted the significant role of focal adhesion signaling in cancer. Nevertheless, its specific involvement in the pathogenesis of endometrial cancer and its clinical significance remains uncertain. We analyzed TCGA-UCEC and GSE119041 datasets with corresponding clinical data to investigate focal adhesion-related gene expression and their clinical significance. A signature, "FA-riskScore," was developed using LASSO regression in the TCGA cohort and validated in the GSE dataset. The FA-riskScore was compared with four existing models in terms of their prediction performance. We employed univariate and multivariate Cox regression analyses towards FA-riskScore to assess its independent prognostic value. A prognostic evaluation nomogram based on our model and clinical indexes was established subsequently. Biological and immune differences between high- and low-risk groups were explored through functional enrichment, PPI network analysis, mutation mining, TME evaluation, and single-cell analysis. Sensitivity tests on commonly targeted drugs were performed on both groups, and Connectivity MAP identified potentially effective molecules for high-risk patients. qRT-PCR validated the expressions of FA-riskScore genes. FA-riskScore, based on FN1, RELN, PARVG, and PTEN, indicated a poorer prognosis for high-risk patients. Compared with published models, FA-riskScore achieved better and more stable performance. High-risk groups exhibited a more challenging TME and suppressive immune status. qRT-PCR showed differential expression in FN1, RELN, and PTEN. Connectivity MAP analysis suggested that BU-239, potassium-canrenoate, and tubocurarine are effective for high-risk patients. This study introduces a novel prognostic model for endometrial cancer and offers insights into focal adhesion's role in cancer pathogenesis.

Fertility After Endometrial Intraepithelial Neoplasia and Early Endometrial Cancer: Ovulation Induction May Shorten Time to Conception

The purpose of this study was to determine whether utilization of assisted reproductive technology following clearance of endometrial intraepithelial neoplasia (EIN) or early endometrial cancer (EC) shortens time to conception (TTC) and reduces recurrence. Patients aged 18 to 45 with EIN or early EC who achieved pathologic response following progesterone treatment were identified via retrospective chart review. Study groups included patients who pursued ovulation induction (OI), in vitro fertilization (IVF), and spontaneous pregnancy. Primary outcomes were TTC and recurrence rate. Three hundred forty-six charts were reviewed, with 86 patients meeting inclusion criteria and 53 attempting pregnancy. Of those 53 patients, 11 became pregnant and seven had a live birth. Median times to pregnancy were 183 days for IVF, 54 days for OI, and 347 days for spontaneous conception (p < 0.05). No differences were seen in recurrence or progression based on attempted pregnancy method, nor with duration of fertility treatment. Forty-two of 86 patients (49%) were lost to follow-up. For patients with a history of treated EIN or EC, OI may decrease TTC. Larger prospective studies are needed to definitively answer this question. Although no differences in recurrence or progression were identified, the significant loss to follow-up rate in this study is concerning and warrants further investigation.

Prognostic Factors of Oncologic and Reproductive Outcomes in Conservative Therapy of Endometrial Hyperplasia and Endometrial Cancer: Systematic Review and Meta-Analysis

Despite broad consensus on the oncological criteria for the inclusion of patients in conservative therapy for endometrial cancer (EC), several prognostic factors affecting patients' subsequent oncological and reproductive outcomes have yet to be explored. To assess the prognostic factors influencing remission, pregnancy and recurrence in conservative therapy of endometrial hyperplasia (EH) and EC. Following the PRISMA statement and the Cochrane Handbook, the search for relevant studies was conducted in PubMed, Embase, Web of Science, Wan fang and China National Knowledge Infrastructure from the inception of the databases to 1 March 2024. Studies that met the inclusion criteria were evaluated for quality using the Newcastle-Ottawa Scale and subsequently analyzed for data extraction. This meta-analysis included 3815 patients with EC or EH treated with conservative therapy in 35 studies. The analysis revealed the overall remission rate of 92.0% (95% CI, 87.0-96.0%), pregnancy rate of 34.0% (95% CI, 32.0-36.0%), and recurrence rate of 27.0% (95% CI, 25.0-29.0%). Four study characteristics, including obesity, pathology type, lesion size, and insulin resistance were associated with remission rate. A total of 8 study characteristics were found to be associated with pregnancy rate, including obesity, pathology type, time to complete response (CR), mode of conception, intrauterine adhesion, the number of uterine manipulations, endometrial thickness and recurrence before pregnancy. Seven study characteristics were found to be associated with recurrence rate, including age over 35.0 years, obesity, family history of cancer, pathological type, abnormal menstruation, pregnancy and maintenance treatment after CR. Common prognostic factors affecting remission, pregnancy and recurrence of endometrial cancer and endometrial hyperplasia are obesity and type of pathology. Patient characteristics, medical factors, and pathological features significantly influence oncological and reproductive outcomes in patients with EH and EC undergoing conservative therapy. Consequently, careful clinical selection and individualized assessment of each candidate for conservative therapy are essential to optimally balance short-term oncological and reproductive outcomes with long-term survival prognosis.

A Primary Low-Grade Vaginal Extrauterine Endometrial Stromal Sarcoma: A Case Report

To analyze the clinical presentation, the diagnostic and therapeutic outcomes of a primary vaginal Low-grade EESS. Managing an LG EESS, such as VESS, is a complex task requiring multi-disciplinary team's involvement. This is crucial to ensure good prognosis due to the non-specific clinical presentations of EESS. A low-grade EESS, such as VESS, requires a multi-disciplinary team to ensure good prognosis. Primary LG-extra-uterine endometrial stromal sarcoma is a rare mesenchymal tumor that can occur at any extra-pelvic site with high recurring rate; therefore, adjuvant therapy such as aromatase inhibitors post-operative is recommended.

miR-1264 Exacerbates Proliferation, Migration and Invasion of Endometrial Cancer Cells by Targeting MSH2

Accumulating studies have revealed that microRNAs serve significant regulatory for endometrial carcinoma (EC) tumorigenesis and progression. The specific objective of this investigation is to seek the potential function of miR-1264 in EC and clarified the underlying mechanism. Determination of miR-1264 and MSH2 expression in EC tissues or cell lines was performed by RT-qPCR and/or western blot assay. The malignant behaviors of EC cells were verified by CCK-8 assay, EdU staining, wound healing assay and Transwell assay, respectively. Besides, the interaction between miR-1264 and MSH2 was verified by dual-luciferase reporter assay and RNA immunoprecipitation assay. MiR-1264 exhibited high levels in EC tissues and has been found to be correlated with a poor prognosis in EC patients. Functionally, silencing miR-1264 resulted in inhibiting the aggressiveness behaviors of HEC-1 A and KLE cells, while forced miR-1264 expression executed opposite effects. Mechanistically, miR-1264 directly targeted and suppressed MSH2 expression. Functional rescue experiments further validated that overexpression of MSH2 diminished malignant behaviors of EC cells and greatly reversed the promoting effects of miR-1264 on the malignant behaviors of EC cells. MiR-1264 acted as an oncogene in EC, promoting aggressiveness behaviors of EC cells by inhibiting MSH2. This study provided novel insights into anti-cancer treatment and a theoretical basis for potential therapeutic targets of EC.

Disulfidptosis-Related lncRNA for the Establishment of Novel Prognostic Signature and Therapeutic Response Prediction to Endometrial Cancer

Disulfidptosis, a newly discovered cellular death mechanism initiated by disulfide stress, features elevated expression of SLC7A11 and restricted glucose availability, rendering it a possible therapeutic target for cancer. Endometrial cancer of the uterine corpus (ECUC) ranks among prevalent gynecological malignancies. Long non-coding RNAs (lncRNAs) have been implicated in ECUC's metabolic pathways, invasive capabilities, and metastatic processes. Yet, the prognostic implications of Disulfidptosis-Linked lncRNAs (DLLs) in ECUC remain ambiguous. Transcriptome and clinical datasets related to ECUC were sourced from The Cancer Genome Atlas (TCGA), while genes linked with disulfidptosis were identified from existing literature. A panel of ten DLLs was discerned through least absolute shrinkage and selection operator (LASSO) coupled with Cox regression methods to formulate and validate risk prognostic models. We engineered a nomogram for ECUC patient prognosis forecasting and further examined the model via gene set enrichment analysis (GSEA), principal component analysis (PCA), gene set analysis (GSA), immune profiling, and sensitivity to antineoplastic agents. Prognostic models employing a set of ten DLLs (including AC005034.2, AC020765.2, AL158071.4, AL161663.2, AP000787.1, CR392039.3, EMSLR, SEC24B-AS1, Z69733.1, Z94721.3) were established. Based on median risk values, patient samples were stratified into high- and low-risk cohorts, revealing notable differences in survival across both training and validation datasets. The risk scores, when amalgamated with clinical variables, acted as standalone predictors of prognosis. GSEA findings indicated that the high-risk category predominantly aligned with pathways like extracellular matrix interactions and cell adhesion molecules, suggesting a likely association with metastatic potential. Concurrently, we scrutinized disparities in immune function and tumor mutational burden across risk categories and identified anticancer drugs with likely efficacy. In summary, a set of ten DLLs proved useful in forecasting patient outcomes and holds potential for informing targeted therapeutic approaches in ECUC.

Prognostic Nutritional Index and the Survival of Patients with Endometrial cancer: A Meta-analysis

The prognostic nutritional index (PNI) has emerged as a potential predictor of clinical outcomes in various cancers. However, a quantativetily analysis of its role in endometrial cancer (EC) remains lacking. This meta-analysis aims to evaluate the prognostic value of PNI on the survival outcomes of patients with EC. A comprehensive literature search was conducted in PubMed, EMBASE, Web of Science, Wanfang, and CNKI to identify relevant cohort studies. Studies were included if they provided sufficient data to calculate hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) based on PNI levels. Data extraction and quality assessment were performed independently by two reviewers. Pooled HRs with 95% confidence intervals (CIs) were calculated using a random-effects model to account for heterogeneity. A total of 10 studies, encompassing 3656 patients, met the inclusion criteria. The meta-analysis revealed that a low PNI was significantly associated with poorer OS (HR = 2.01, 95% CI = 1.62-2.49, p < 0.05; I

The Identification of Gamma-Glutamyl Hydrolase in Uterine Corpus Endometrial Carcinoma: a Predictive Model and Machine Learning

Poor neoplastic differentiation contributes to the rapid progression of uterine corpus endometrial carcinoma (UCEC). Thus, it is essential to identify candidate genes, clarifying the carcinogenesis and progression of UCEC. We screened genes that affect differentiation and prognosis in UCEC. Least absolute selection and shrinkage operator (LASSO) regression, univariate Cox, and multivariate Cox proportional risk regression analyses were performed to screen out γ-glutamyl hydrolase (GGH) as the candidate gene. The clinical value of GGH on prognosis was evaluated. The relationship between GGH and immune infiltration was assessed by CIBERSORT, EPIC, ssGSEA, unsupervised clustering and immunohistochemistry (IHC). Additionally, we investigated the effect of GGH knockdown in vitro. Among the GGH, CDKN2A, and SIX1 genes, the impact of GGH was predominant on immune infiltration in UCEC. A nomogram containing GGH and other clinical features showed good predictive performance via curve analysis (DCA). In the functional analysis, GGH affected differentiation, tumour proliferation, and immune regulation. The immunosuppressive components were enriched in the GGH-high group, with poor immunotherapy efficacy. The study suggests that GGH may influence the progression of UCEC by regulating the glycolytic process. GGH is closely associated with various immune cell infiltrations. Our study demonstrates the prognostic role of GGH in carcinogenesis in UCEC.

Association of Urinary Levels of Estrogens and Estrogen Metabolites with the Occurrence and Development of Endometrial Hyperplasia Among Premenopausal Women

Endometrial cancer is known to be an estrogen-dependent cancer, and it is believed that exposure to estrogens increases the risk of developing endometrial cancer in the absence of progesterone. Estrogens and estrogen metabolites may help to predict the risk of endometrial hyperplasia (EH) with atypia. Estrogens and estrogen metabolites were measured by high-performance liquid chromatography-mass spectrometry (HPLC-MS/MS) in the first morning urine sample collected from 150 patients with EH and 50 healthy premenopausal women in the study. In healthy premenopausal women, the level of 16α-hydroxyestrone (16α-OHE1) in the overweight group was significantly higher than that in the lean group (p < 0.05). The levels of 4-hydroxyestradiol (4-OHE2) and 16α-OHE1 were elevated in the AEH group as compared to that in the control group (p < 0.05). Overweight is related to EH incidence as it causes an imbalance of estrogen metabolites. This study provides identifies potential biomarkers for estrogen-induced AEH.

Total Sialic Acid, Antioxidant Enzyme Activities, Trace Elements, and Vitamin Status Before and After Surgery in Women with Uterine Myoma and Endometrial Cancer

The objective of present study was to examine endometrial tissue Be, As, Cr, Mo, Sr, Ti, Tl, Cu, Co, Se, Zn, Mn, Fe, Cd, Pb, Mg, P, erythrocytes CAT, SOD, GSH-Px, GSH, MDA, serum retinol, cholecalciferol, phylloquinone, TSA, LSA, TOS, and TAS status and to evaluate the relationships between the variables. The study had 110 participants; of these, 50 were women with uterine myoma (UM), 10 were women with endometrial cancer (EC), and 50 were healthy female subjects. In the study, vitamin analyses by HPLC and element analyses were determined using ICP-OES method. It was observed that EC group was significantly lower than healthy group in terms of levels of cholecalciferol (p < 0.05), phylloquinone (p < 0.01), GSH (p < 0.05), Fe (p < 0.05), and had a significant rise in Mg/Fe (p < 0.01) and Zn/Fe (p < 0.05) in preoperative period. UM group had significantly lower retinol (p < 0.05), phylloquinone (p < 0.001), GSH-Px (p < 0.01), GSH (p < 0.01), Cr (p < 0.01), Cu (p < 0.05), Mg (p < 0.01), and Zn (p < 0.01) levels than control group in preoperative period and significantly higher levels of MDA (p < 0.01), TSA (p < 0.01), and LSA (p < 0.01) than control group. It was found that significant associations were observed between Cu-CA 15-3 (r = 0.558, p = 0.016), Mn-CA 15-3 (r = 0.511, p = 0.030), P-CA 15-3(r =  - 0.502, p = 0.034) and with UM, also between GSH-CA-125 (r =  - 0.825, p = 0.022) and with EC group. The results of correlation analysis observed that concentrations of Cu, Mn, P, and GSH together with CA 15-3 and CA-125 levels might be important for monitoring patients with UM and EC before surgery.

LncRNA-LA16c-313D11.11,A Signature to Predict Endometrial Carcinoma Patients with a Better Survival

The aim of this study was to develop and internally validate a nomogram of the probability EC patients surviving longer than 5 years. Quantitative real-time PCR (qRT-PCR) was implemented to analyze the expression of lncRNA-LA16c-313D11.11 in 60 EC tissues. The clinicopathological characteristics and follow-up data were retrospectively gathered and analyzed. To establish the prediction model, multivariate logistic regression analysis was applied, and the discrimination, calibration, and clinical practicability of the prediction model were assessed with a concordance index (C-index), calibration chart, and decision curve analysis. Bootstrap validation was performed for internal validation. The prediction factors included the age of patients, myometrial invasion, lymphovascular space invasion, histological subtype, and the expression of lncRNA-LA16C-313D11.11. The model demonstrated good calibration and modest discrimination (C-index = 0.860, 95% confidence interval: 0.724-0.946). Moreover, the interval validation achieved a high C-index value of 0.778. This study revealed the predictive value of lncRNA-LA16C-313D11.11 and successfully developed a nomogram for predicting EC patients survival longer than 5 years, which may facilitate the institution of personalized treatment algorithms, surveillance strategies, and lifestyle interventions.

Heat Shock Protein B7 Inhibits the Progression of Endometrial Carcinoma by Inhibiting PI3K/AKT/mTOR Pathway

To investigate the role and mechanism of action of Heat shock protein B7 (HSPB7) in endometrial carcinoma (EC). GEPIA (Gene Expression Profiling Interactive Analysis) was used to analyze the expression and prognostic value of HSPB7 in TCGA data. HSPB7 mRNA and protein expression levels were detected by qRT-PCR and Western blot, respectively. EC cell proliferation, apoptosis, migration, and invasion were determined by colony formation, EdU, flow cytometry, and transwell assays. Mitochondrial membrane potential was determined using JC-1 probe. In addition, apoptosis-related and metastasis-related proteins were quantitatively evaluated. A gene set enrichment analysis of the signaling pathways by which HSPB7 influences EC was performed and the levels of enriched pathway-related proteins were evaluated. We first proved that HSPB7 was downregulated in EC tissues and HSPB7 levels were positively related to survival rates. In functional assays, HSPB7 overexpression suppressed the proliferation, migration, and invasion of EC cells and conversely promoted apoptosis. Moreover, HSPB7 overexpression decreased the mitochondrial membrane potential of EC cells significantly. Bioinformatics analyses revealed that the PI3K/AKT/mTOR pathway was significantly enriched in EC. HSPB7 inhibited the phosphorylation of the PI3K/AKT/mTOR pathway to reduce proliferation, migration and invasion, and increased apoptosis in EC cells. HSPB7 was downregulated in EC and influenced EC cell proliferation, invasion, migration, and apoptosis via the PI3K/AKT/mTOR signaling pathway. These findings provide a novel perspective for the development of EC treatment strategies.

Endometrial Cancer Following Levonorgestrel-Releasing Intrauterine System Insertion in Young Women with Atypical Hyperplasia: Two Case Reports and Literature Review

Levonorgestrel-releasing intrauterine system (LNG-IUS) insertion is the first-line treatment for atypical hyperplasia (AH) in young women who wish to retain their fertility. However, the procedure is not always effective, and may allow AH to progress to endometrioid endometrial cancer (EEC). Two young women with AH who wished to preserve their fertility developed EEC following 52-mg LNG-IUS in insertion at our institution. One was a 34-year-old woman diagnosed with endometrial cancer 2 years after LNG-IUS insertion. The second was a 30-year-old woman diagnosed 17 months after LNG-IUS insertion. Proactive molecular risk classification for endometrial cancer (ProMisE) classification revealed that the first and second patients had p53-abnormal (p53abn) EEC and mismatch repair deficient (MMR-d) EEC, respectively. MMR-d and p 53abn were frequently observed in both AH and EEC specimens. Studies suggest that MMR-d and p53abn are predictors of the occurrence adverse effects after fertility-preserving treatment for EEC. AH is a precursor of EEC. Therefore, p53 and mismatch repair (MMR) mutation may be used to identify women with AH who will not likely benefit from progestin therapy. Molecular assays in women with AH will likely be useful for identifying novel predictive biomarkers of progestin resistance and to improve the safety of conservative treatment. Combined assessment of progesterone receptor (PR) with these predictive molecular markers may improve the predictive ability.

The Prediction of Recurrence in Low-Risk Endometrial Cancer: Is It Time for a Paradigm Shift in Adjuvant Therapy?

Five to 10% of patients with stage IA, grade 1 or 2, endometrioid adenocarcinoma subsequently develop locoregional or distant recurrence. These patients have significantly reduced 5-year survival rates and salvage therapy success rates as low as 40%. The aim of this review is to highlight knowledge gaps that could further refine the risk categories of endometrial carcinoma (EC) and guide future randomized trials of adjuvant therapy for low-risk EC. A systematic search of the literature on PubMed and Medline was conducted using the following search terms: endometrial cancer, endometrial adenocarcinoma, endometrioid adenocarcinoma, low grade, early stage, stage IA, low risk, locoregional recurrence, and relapse. Relevant primary studies were extracted and included in this review. Risk factors for recurrence of low-risk EC were epidemiological (age, body mass index, ethnicity), molecular (DNA MMR, MSI, TP53 mutation and P53 defect, CTNNB1 mutation, PTEN and POLE mutation, L1CAM expression), pathological (positive peritoneal cytology, lymphovascular invasion, tumor size), and others like Ki67-percentage, micro-RNA expression, and hormonal receptor expression. CTNNB1 mutation, L1CAM expression, lymphovascular invasion, and tumor size were identified as significant risk factors for recurrence in low-risk EC. There are subsets of low-risk EC patients at high risk of recurrence and should be suspected when having the following risk factors: positive molecular markers, large tumor size, and lymphovascular invasion. A novel scoring system and randomized controlled trials should be conducted to identify these patients who will benefit most from adjuvant therapy to avoid recurrence.

MiR-192-5p-Modified Tumor-Associated Macrophages-Derived Exosome Suppressed Endometrial Cancer Progression Through Targeting IRAK1/NF-κB Signaling

Tumor-associated macrophages (TAMs) are a major regulator in the development of endometrial cancer (EC). It was indicated that TAMs could crosstalk with cancer cells via transferring exosomes which carrying microRNAs (miRNAs). Firstly, we found that TAMs could promote the epithelial-mesenchymal transition (EMT) of EC cells and inhibit its apoptosis. Next, we further found that TAMs regulated the EMT and apoptosis of EC cells through transferring exosomes into EC cells. Then, lowly expressed miR-192-5p in TAMs-derived exosomes was proved. Moreover, our data demonstrated that upregulation of miR-192-5p in TAMs-derived exosomes could significantly promote the apoptosis of EC cells and impede its EMT. IRAK1 was proved to be a downstream target of miR-192-5p. Importantly, we indicated that miR-192-5p-overexpressed TAMs-derived exosomes regulated the EC cells apoptosis and EMT through inhibiting IRAK1/NF-κB signaling pathway. In addition, we also revealed that overexpression of miR-192-5p in TAMs-derived exosomes obviously limits the growth of tumors. Overall, in TAMs-derived exosomes, our data demonstrated that overexpression of miR-192-5p could effectively suppress the progression of EC. Our data provid a new target for EC treatment.

Regional Proteomic Characterization of Uterine Leiomyomas: Implications for Molecular Pathways and Tumor Biology

Uterine leiomyomas are the most common benign smooth muscle tumors in women of reproductive age. Recent technological advances have enhanced the potential of proteomic studies to identify proteins and related signaling pathways involved in leiomyoma pathogenesis. This study performed comprehensive proteomic analyses of three leiomyoma subtypes, classified by their localizations, to provide new insights and a valuable resource for further studies. Tissue samples from both leiomyoma and normal myometrial tissues were collected from individuals undergoing hysterectomy for symptomatic leiomyomas. Proteins were extracted from tissue samples, enzymatically digested to generate peptides, and subsequently analyzed using high-resolution mass spectrometry (HR-MS). Biological significance and related pathways of differentially expressed proteins were revealed by Gene Ontology (GO) analyses. MS analyses revealed significant expression changes in 143, 152 and 146 proteins in submucosal, subserosal and intramural myomas, respectively. Top enriched categories of dysregulated proteins included RNA binding, oxidoreductase activity, cytoskeletal structural components, glutathione transferase activity, extracellular matrix organization, innate immunity, post-translational phosphorylation. The classification of differentially expressed proteins (DEPs) also highlighted the metabolite interconversion enzyme family in all three groups. Hydrolase, oxidoreductase and transferase subfamilies were common to all three groups, while isomerase, ligase and lyase subfamilies were present in the subserosal and intramural groups. Proteomic analyses provided important information about the dysregulated proteins in uterine leiomyomas and revealed various pathways to which they are related. The findings emphasize the need for further research, especially on the effects of oxidative stress on the immune response against tumor cells, the role of extracellular matrix proteins and enzymes in metabolic pathways.

Identification of hub genes and potential molecular mechanisms of tumor immune microenvironment-related radiotherapy sensitivity in locally advanced cervical cancer

Cervical cancer remains the most prevalent malignancy of the female reproductive system; however, the five-year survival rate has not improved substantially over recent decades. This persistent challenge highlights the critical need to elucidate mechanisms underlying treatment sensitivity and investigate synergistic effects of multimodal therapies to overcome clinical therapeutic bottlenecks. By conducting a comprehensive analysis of The Cancer Genome Atlas (TCGA) database, this study identified a hub gene network associated with radiotherapy sensitivity in cervical cancer. In addition to developing a personalized treatment prediction model, we preliminarily characterized these hub genes through several key dimensions: molecular regulatory, biological functions, tumor microenvironment infiltration patterns, and immune relevance. Notably, this work is the first to reveal that hub genes such as DDX58 probably orchestrate a tripartite regulatory mechanism-mediated by immune microenvironment factors-that concurrently influences sensitivity to radiotherapy, chemotherapy, and immunotherapy. Through a series of analyses, we speculate that these hub genes can serve not only as combined biomarkers for predicting responses to multiple therapies but also as novel molecular targets for the development of synergistic treatment strategies via their mediated immune microenvironment interactions. These findings provide a new translational research direction for overcoming therapeutic resistance in cervical cancer.

Construction and Validation of a Novel Prognostic Model Based on Cervical Cancer-Related Genes

Cervical cancer (CC) is the fourth most frequently diagnosed cancer and the fourth leading cause of cancer-related deaths in women worldwide, however, the treatment options for advanced CC are limited. Therefore, there is an urgent need in the clinic for reliable prognostic models to guide clinical decision-making. We conducted differential gene expression analysis on cervical cancer samples and normal samples to obtain differentially expressed genes (DEGs). We used WGCNA analysis to identify the most relevant module associated with cervical cancer and intersected with DEGs to obtain cervical cancer-related genes. We then constructed a protein-protein interaction (PPI) network using these genes and identified core genes using the Hubba plugin in Cytoscape software. Subsequently, we built a prognostic model using the identified cervical cancer-related genes in combination with the TCGA database. GSE44001 was used to verify the accuracy of the model. We performed a single-gene survival analysis on the genes involved in model construction. We obtained 52 cervical cancer-related genes and 22 core genes (DNA2, CEP55, GINS1, RFC4, KIF14, GINS2, MYBL2, KIF4A, RAD54L, KNTC1, SPAG5, MELK, CENPE, MCM2, NCAPH, MCM5, ASPM, HELLS, DTL, FOXM1, TOP2A, CDC45). We successfully constructed a prognostic model using cervical cancer-related genes. The comprehensive analysis showed that the constructed prognostic model could effectively predict the prognosis of cervical cancer patients, with AUC values of 0.858, 0.802, and 0.797 for 1, 3, and 5 years in the training group, respectively. The results were consistent in the validation using the GSE44001 dataset. Single-gene survival analysis showed that APOD was an independent prognostic biomarker for cervical cancer. APOD is a prognostic biomarker for cervical cancer, and the prognostic model constructed by identified cervical cancer-related genes can successfully distinguish the prognosis of patients with cervical cancer.

Can a Diet, Nutrition and Supplement Program Prevent Uterine Fibroid Recurrence? Pilot Results of the LIFE Program

The objective of this prospective, longitudinal cohort study was to evaluate the pilot effects of a 24-month exercise and nutrition intervention, called the Lifestyle Intervention for Fibroid Elimination Program (LIFE), at NYU Langone Health's Center for Fibroid Care. Specifically, we evaluate the impact on quality of life (QOL), symptom severity (SS), and clinical lab markers in 22 fibroid patients. Patients who underwent a procedure within 3 months of the start of the LIFE Program and completed up to 12 months of the program were included in this study. Participants were excluded if currently pregnant, postmenopausal, or had dietary restrictions or physical constraints that prevented them from participating fully in the intervention. This intervention required participants to follow a prescribed nutrition and exercise regimen for up to 12 months and attend at least 2 office visits with a physician. Participants also completed two quality of life questionnaires and regular ultrasound imaging. The demographic breakdown of our study cohort was 63.6% Black and 18.2% Hispanic/LatinX. A clinically meaningful improvement in QOL and symptom severity was found within the first year of the LIFE program. The QOL sub-scale scores that showed the greatest improvement were concern and energy/mood. Vitamin D lab values also showed a clinically meaningful improvement. The LIFE Program was associated with a reduction in symptom burden and an improvement in quality of life up to 12 months after a procedural fibroid intervention, yielding insight into how a lifestyle intervention may be an effective adjunct in improving patient quality of life.

Using Machine Learning to Predict the Prognosis of Cervical Cancer Patients with Lymph Node Metastasis: An Analysis Based on the SEER Database

Cervical cancer is one of the most common malignant tumors in women worldwide, and patients with lymph node metastasis have a poor prognosis. This study aimed to develop an effective machine learning model to predict the prognosis of these patients. Data from the SEER*Stat database (version: November 2021) was used, including 1016 female patients diagnosed with cervical cancer and lymph node metastasis from 2000 to 2020. Various machine learning models, including XGBoost, random forest, SVM, ANN, and the Cox proportional hazards model, were constructed and evaluated using metrics such as C-index, AUC, accuracy, and precision. Additionally, to validate model stability, a random sample of 200 patients from 8 registries between 1975 and 2019 was used as a validation set. XGBoost outperformed other models with an AUC of 0.787 in the validation set and C-index values of 0.900 and 0.773 for the training and testing sets, respectively. Cox regression analysis showed that surgery at the primary site significantly improved survival outcomes and reduced mortality. XGBoost demonstrated superior performance in predicting the prognosis of cervical cancer patients with lymph node metastasis, providing new support for personalized clinical management.

Combined Effects of Annexin A5 Overexpression, 5-Fluorouracil Treatment, and Irradiation on Cell Viability of Caski Cervical Cancer Cell Line

Cervical cancer is the fourth leading cause of cancer deaths in women globally. Combining gene therapy with chemo- and radiotherapy may improve cervical cancer treatment outcomes. This study evaluated the effects of Annexin A5(ANXA5) overexpression alongside 5-fluorouracil (5-FU) and irradiation on the viability of CaSki cervical squamous cell carcinoma (SCC) cells. pAdenoVator-CMV-ANXA5-IRES-GFP-plasmid and mock plasmid were transfected into CaSki cells using calcium-phosphate. Seventy-two hours post-transfection, GFP expression was quantified by fluorescence microscopy and flow cytometry to evaluate transfection efficiency. ANXA5 overexpression was confirmed via qPCR. Twenty-four hours post-transfection, cells received a single dose of 8 Gy and were treated with 1 and 2 µg/ml of 5-FU (IC50 = 2.783 µg/ml). Cell viability, apoptosis, cell cycle stage, and Bcl-2 and Bax gene expression were assessed via MTT, annexin V/7-AAD, PI staining, and qPCR assays, respectively. ANXA5 was overexpressed 31.5-fold compared to control (p < 0.0001). MTT assays showed ANXA5 overexpression dose-dependently reduced CaSki cell viability (p < 0.001). IC50 of 5-FU was reduced from 2.783 μg/mL to 1.794 μg/mL when combined with ANXA5 overexpression. Additive effects on cell death were observed for ANXA5 plus 5-FU or irradiation versus ANXA5 alone. Apoptosis assays indicated combinatorial treatment increased CaSki cell apoptosis over ANXA5 alone. Cell cycle analysis revealed ANXA5 arrested cell cycle at G1/S phases; the percentage of cells in the S phase further rose with combination treatment. Finally, combination therapy significantly decreased Bcl-2 expression and increased Bax versus control (p < 0.001). Altogether, ANXA5 overexpression alongside 5-FU and irradiation may improve cervical squamous cell carcinoma (SCC) treatment efficacy. Further, in vivo investigations are warranted to confirm these in vitro results.

The Expression of Programmed Cell Death Ligand-1 and its Relationship with Infiltration, Metastasis and Prognosis in Cervical Squamous Cell Carcinoma

Cervical cancer (CC) represents a major gynecologic health problem. Respecting the role of programmed cell death ligand-1 (PDL-1) in cancer prognosis, we investigated its relationship with cervical squamous cell carcinoma (CSCC) invasion, metastasis and prognosis. A total of 184 CSCC patients were retrospectively selected, with normal paracarcinoma tissues as the Control group. PDL-1 expression was assessed, and its relationship with CSCC prognosis and clinical value on predicting CSCC invasion/metastasis and poor prognosis were determined. PDL-1 was up-regulated in CSCC. CSCC patients at International Federation of Gynecology and Obstetrics stage II/III, and with lymph node metastasis (LNM), parauterine/vascular infiltration, and history of sexually transmitted diseases exhibited up-regulated PDL-1. The areas under the curve of PDL-1 on predicting the invasion and metastasis/poor prognosis of CSCC patients were 0.930 (95%Cl: 0.883-0.962)/0.935 (95%Cl: 0.886-0.967), with cut-off values of 23.27/24.86 (86.76%/80.95% sensitivity, 95.69%/92.68% specificity). The CSCC patients with highly-expressed PDL-1 showed increased cumulative incidence of poor prognosis. Additionally, occurence of vascular infiltration/LNM, and up-regulated PDL-1 were independent risk factors for poor prognosis in CSCC patients. Briefly, PDL-1 expression rised in CSCC. High PDL-1 expression might promote tumor infiltration and LNM, while close monitoring of its expression contributed to evaluating prognosis of CSCC patients.

Establishment of 3D Cultures of Myometrium, Leiomyoma, and Leiomyosarcoma Cells: Advantages and Disadvantages of Two Different Models

Uterine leiomyomas are the most common benign, monoclonal, gynaecological tumors in a woman's uterus, while leiomyosarcoma is a rare but aggressive condition caused by the malignant transformation of the myometrium. To overcome the common obstacles related to the methods usually used to study these pathologies, we aimed to devise three-dimensional models of myometrium, uterine leiomyoma and leiomyosarcoma cell lines, using two different types of biocompatible scaffolds. Specifically, we exploited the agarose gel matrix in common 6-well plates and the alginate matrix using Bioprinting INKREDIBLE + (CELLINK), a pneumatic extruded base equipped with a system with double printheads, and a UV printer LED curing system. Both methods allowed the development of 3D spheroids of all three cell types, that were also suitable for morphological investigations. We showed that all cell types embedded in both agarose and alginate formed spheroids in their growth medium. The spheroids successfully proliferated and self-organized into complex structures, developing a sustainable system that emulated the condition of the tissues through the accumulation of extracellular matrix. These models could be useful for a better understanding of pathophysiology, etiopathogenesis, and testing new methods or molecules from a preventive and therapeutic point of view.

Association of HOTAIR rs7958904 Polymorphism with Cervical Cancer Risk

Cervical cancer (CC) has been the prominent cause of cancer-associated fatalities among women in developing countries. In terms of occurrence and mortality, it is ranked second in Bangladesh. Although different genetic polymorphisms linked with this cancer have been investigated over time, the association between the HOTAIR rs7958904 variant and cervical cancer is being reported for the first time in Bangladeshi women. RT-PCR-based TaqMan assay was employed to perform this case-control study on 200 cervical cancer patients and 148 healthy volunteers. Both cases and controls had average ages of 57.5 and 52.5 years, respectively. According to Hardy-Weinberg equilibrium, the rs7958904 allele of HOTAIR gene pretended no deviation for both cases and control groups. The genotyping results showed that rs7958904 has a significant correlation to the development of cervical cancer in different genetic association models, such as co-dominant 1 (CC vs. GG: OR = 1.67, p = 0.0435), co-dominant 2 (CC vs. GG: OR = 3.13, p = 0.0006), co-dominant 3 (CC vs. CG: OR = 1.88, p = 0.0384), dominant (CG + CC vs. GG: OR = 1.98, p = 0.004), recessive (CC vs. GG + CG: OR = 2.25, p = 0.005), and allele model (C vs. G: OR = 1.70, p = 0.0006). In conclusion, the HOTAIR rs7958904 variant has a substantial role in cervical cancer development in Bangladeshi women. Further functional studies with a larger population size are required to support our findings.

Targeting Bromodomain-Containing Protein 9 in Human Uterine Fibroid Cells

Bromodomain (BRD)-containing proteins are evolutionarily conserved protein-protein interaction modules involved in many biological processes. BRDs selectively recognize and bind to acetylated lysine residues, particularly in histones, and thereby have a crucial role in the regulation of gene expression. BRD protein dysfunction has been linked to many diseases, including tumorigenesis. Previously, we reported the critical role of BRD-containing protein 9 (BRD9) in the pathogenesis of UFs. The present study aimed to extend our previous finding and further understand the role of the BRD9 in UFs. Our studies demonstrated that targeted inhibition of BRD9 with its potent inhibitor TP-472 inhibited the pathogenesis of UF through increased apoptosis and proliferation arrest and decreased extracellular matrix deposition in UF cells. High-throughput transcriptomic analysis further and extensively demonstrated that targeted inhibition of BRD9 by TP-472 impacted the biological pathways, including cell cycle progression, inflammatory response, E2F targets, ECM deposition, and m

Circ_TMCO3 Inhibits the Progression of Cervical Cancer by Activating FRMD6 Expression by Restraining miR-1291

Cervical cancer (CC) is one of the most common cancers that threaten the life of women. More and more circular RNAs (circRNAs) have been found to be maladjusted in tumor tissues. However, the mechanism of circ_TMCO3 in CC needs to be studied. In this study, quantitative real-time polymerase chain reaction (qRT-PCR), western blot, and immunohistochemistry (IHC) were used to detect the expressions of circ_TMCO3, miR-1291, and FERM domain-containing protein 6 (FRMD6). Cell viability, proliferation, apoptosis, migration, invasion, and protein level were detected via 3-(4, 5-dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT), 5-Ethynyl-2

ceRNA Network and WGCNA Analyses of Differentially Expressed Genes in Cervical Cancer Tissues for Association with Survival of Patients

The study aims to search and identify differentially expressed genes (DEGs) in cervical cancer tissues as novel biomarkers to predict cervical cancer prognosis. The Cancer Genome Atlas (TCGA) data on gene expression profiles in cervical cancer were downloaded and analyzed using R software to identify DEGs in cervical cancer tissues. miRNAs targeted by differentially expressed long non-coding RNAs (DElncRNAs) and mRNAs targeted by microRNAs (miRNAs) were identified using the online miRcode, miRTarBase, TargetScan, and miRDB tools. The ceRNA network and lncRNA expression modules in cervical cancer tissues were constructed using weighted gene co-expression network analysis (WGCNA) and analyzed bioinformatically. The Kaplan-Meier analysis was performed to confirm these DEGs as prognostic markers. Immunohistochemical (IHC) analysis was used to verify expression of the hub genes in 10 paired cervical cancer and normal tissues. A total of 1914 DEmRNAs, 210 DElncRNAs, and 67 DEmiRNAs were identified in cervical cancer samples. There were 39 lncRNAs, 19 miRNAs, and 87 mRNAs involved in the ceRNA network and 25 DElncRNAs, three DEmiRNAs, and four mRNAs involved in the ceRNA sub-network. CACNA1C-AS1 was associated with the yellow and blue modules in the ceRNA sub-network, and LIFR-AS1 was associated with the blue module. The DEmRNAs were involved in cancer-related pathways, and three hub genes (i.e., E2F1, CCNB1, and CCNE1) were highly expressed in cervical squamous cell carcinoma and adenocarcinoma tissues and associated with the prognosis of patients. The ceRNA network and WGCNA analyses are useful to identify novel DEGs that can serve as prognostic markers in cervical cancer. The DEGs will be validated in future studies.

Multilevel Transcriptomic Association Analysis Reveals Key Genes and Potential Mechanisms in Endometrial, Ovarian, and Cervical Cancers

Abstract Objective: This study aims to investigate the genetic associations of endometrial cancer (EC), ovarian cancer (OC), and cervical cancer (CC), identify potential key genes using multiple genomic analysis approaches, and analyze their roles in cancer development. Methods: We integrated large-scale genome-wide association study (GWAS) data from Jiang L et al. and Zhou W et al., combined with blood eQTL data. We employed S-PrediXcan, SMR, and mBAT-combo to assess gene associations with EC, OC, and CC. Additionally, RNA sequencing data were used to analyze the expression levels of key genes across different tissues, followed by functional enrichment analysis to explore their potential biological functions. Results: Through S-PrediXcan, SMR, and mBAT-combo analyses, we identified 690, 620, and 624 genes associated with OC, CC, and EC, respectively. Among them, 79, 59, and 61 genes were consistently significant across all three methods, suggesting their crucial roles in cancer development. Furthermore, we identified multiple comorbidity-related genes, including SPX, which exhibited a negative association with OC, CC, and EC. Transcriptomic analysis revealed that 26 key genes displayed significant expression differences between tumor and normal tissues. Functional enrichment analysis further identified the molecular pathways potentially involved. Conclusion: This study identified a set of key genes associated with EC, OC, and CC and suggested that SPX may play a protective role in cancer development. The integration of multilevel genetic and transcriptomic analyses provides new insights into the molecular mechanisms underlying gynecological malignancies and offers potential biomarkers for future precision medicine research.

Unmasking the Hypoxia Landscape in Cervical Cancer: S100A2 and Its Implication for Immunotherapy Resistance

AbstractCervical cancer is the fourth most common cancer in women worldwide and typically diagnosed between the ages of 35 and 44. Despite the death rate declining 1% each year since the 2000s, the 5-year survival of late stage remains lower than 20%. This emphasizes the urgency to keep exploring cervical cancer cell survival factors and identifying new prognostic markers. In this issue of Reproductive Sciences, Yang et al. stratified hypoxia subtype by analyzing 200 hypoxia-related genes in TCGA database and observed patient overall survival, hypoxic, transcriptome, genomics, and immunological characteristics vary among these hypoxia subtypes and created a hypoxia score which successfully stratified patient by predicting clinical outcomes and response to immunotherapy. Simultaneously, a hypoxia mediator (S100A2) associated with an aggressive cervical cancer phenotype is identified. We reviewed similar work on S100A2 and hypoxia-mediated multidrug resistance and highlighted the values added by this study. Future work could focus on unraveling the direct link between S100A2 and immunotherapy resistance.

A Cellular Senescence-Related Signature Predicts Cervical Cancer Patient Outcome and Immunotherapy Sensitivity

Abstract Cervical cancer (CC) is one of the most prevalent gynecological malignancies. The rate of mortality and morbidity among patients with CC is high. Cellular senescence is involved in tumorigenesis as well as in the cancer progression. However, the involvement of cellular senescence in CC development is still unclear and requires further investigation. In this study, we retrieved data on cellular senescence-related genes (CSRGs) from the "CellAge" Database. We used the TCGA-CESC and CGCI-HTMCP-CC datasets as the training and validation sets, respectively. Finally, a signature was constructed using "univariate" and "Least Absolute Shrinkage and Selection Operator" (LASSO) Cox regression analysis, which contains eight CSRGs. Using this signature, we calculated the risk scores of all patients in the training and validation cohorts and categorized them into the low-risk group (LR-G) and the high-risk group (HR-G). Results showed that, compared to patients in the HR-G, those in the LR-G demonstrated a more positive clinical prognosis, more abundant immune cell infiltrations, and a more active immune response. The signature could also modulate the expression of SASP factors. In vitro studies showed an increased expression of SERPINE1 and IL-1α genes included in the signature in CC cells and tissues. Our findings help to deepen our insights into the etiology of CC, which could be beneficial for prognostic prediction and immunotherapy in clinical practice.

Noncoding RNA (ncRNA) Profile Association with Patient Outcome in Epithelial Ovarian Cancer Cases

AbstractOvarian cancer (OC) is the second most frequent type of gynecological cancers worldwide. In the past decades, the development of novel diagnostic and prognostic biomarkers available for OC has been limited, reflecting by the lack of specificity of such markers or very costly management. Microarray expression profiling has shown very effective results in exploring new molecular markers for patients with OC. Nonetheless, most screenings are focused on mutations or expression of molecules that are translated into proteins, corresponding to only 2% of the total human genome. In order to account for the vast majority of transcripts, in the present exploratory study, we assessed the expression levels of a comprehensive panel of noncoding RNA in different subtypes of OC. We further evaluated their association with patient overall survival (OS) and aggressive forms of the disease, such as tumor type, stage, and chemotherapy resistance. By microarray profiling in a total of 197 epithelial OC patients (162 serous carcinomas, 15 endometrioid carcinomas, 11 mucinous carcinomas, and 9 clear cell carcinomas), we found two candidates, SNORA68 and SNORD74, which associated with OS and poor clinicopathological features. The overexpression of those two targets combined was correlated with shorter OS and progression-free survival. That association was further observed to correlate with a more aggressive form of the disease. Overall, the results indicate that a panel comprised of SNORA68 and SNORD74 may be clinically relevant, where patients could be offered a more individualized, targeted follow-up, given its further validation on future prospective clinical studies.

Hsa_circ_CSPP1/MiR-361-5p/ITGB1 Regulates Proliferation and Migration of Cervical Cancer (CC) by Modulating the PI3K-Akt Signaling Pathway

This study aimed to investigate the regulatory mechanism of circular RNA CSPP1 (hsa_circ_CSPP1) in cervical cancer. Based on GEO database, differentially expressed circRNAs and mRNAs related to cervical cancer were screened out by R software. Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis and Gene Ontology (GO) term analysis were performed to analyze the functional and pathway enrichment of identified DEGs. In addition, Cytoscape software was used to build interaction network of DEGs. The mRNA expressions were examined by qRT-PCR. Western blot was conducted to view the expression of proteins. Cell proliferation and apoptosis were respectively evaluated using CCK-8 assay and flow cytometry, whereas cell migration abilities were detected by Transwell assay. The relationship among factors was validated by dual-luciferase reporter gene assay. The influence in cervical tumor growth was further verified through nude mouse model in vivo. Hsa_circ_CSPP1 and ITGB1 were high-expressed in cervical cancer, while miR-361-5p was low-expressed. Hsa_circ_CSPP1 knockdown or miR-361-5p overexpression could suppress cervical cancer cell proliferation and migration, whereas promoted cell apoptosis. In addition, further experiments demonstrated that both hsa_circ_CSPP1 and ITGB1 mRNA were targets of miR-361-5p. Repressing hsa_circ_CSPP1 restrained cell viability and mobility and induced apoptosis through sponging miR-361-5p. Meanwhile, miR-361-5p also inhibited cervical cancer tumorigenesis via downregulation of ITGB1. Knockdown of hsa_circ_CSPP1 impeded tumor growth through suppressing the expression of downstream gene ITGB1, PI3K, and Akt. Circular RNA hsa_circ_CSPP1 regulates cell migration and proliferation in cervical cancer through miR-361-5p/ITGB1 in PI3K-Akt signaling pathway.

LncRNA BLACAT1 Is Upregulated in Cervical Squamous Cell Carcinoma (CSCC) and Predicts Poor Survival

The function of oncogenic lncRNA BLACAT1 has been studied in several types of cancer, while its role in cervical squamous cell carcinoma (CSCC) is unknown. We showed that BLACAT1 was upregulated in CSCC tissue comparing to adjacent non-cancer tissue of CSCC patients. BLACAT1 expression in CSCC tissues was not affected by HPV infection. Patients with higher BLACAT1 level in CSCC tissues showed a significantly lower overall 5-year survival rate. BLACAT1 expression was inversely correlated with several tumor-suppressive miRNAs, such as miR-424 and miR-143. miR-424 and miR-143 overexpression did not significantly affect BLACAT1, while BLACAT1 overexpression caused downregulated miR-424 and miR-143. Overexpression of miR-424 and miR-143 led to inhibited migration and invasion, while BLACAT1 overexpression led to promoted migration and invasion of CSCC cells. In addition, overexpression of miR-424 and miR-143 attenuated the effects of BLACAT1 overexpression. Therefore, BLACAT1 overexpression may promote CSCC by downregulating miR-424 and miR-143.

Metformin Promotes Anti-tumor Biomarkers in Human Endometrial Cancer Cells

AbstractMetformin (MET) is increasingly implicated in reducing the incidence of multiple cancer types in patients with diabetes. However, similar effects of MET in non-diabetic women with endometrial cancer (EC) remain unknown. In a pilot study, obese non-diabetic women diagnosed with type 1, grade 1/2 EC, and consenting to participate were randomly assigned to receive MET or no MET (control (CON)) during the pre-surgical window between diagnosis and hysterectomy. Endometrial tumors obtained at surgery (MET, n = 4; CON, n = 4) were analyzed for proliferation (Ki67), apoptosis (TUNEL), and nuclear expression of ERα, PGR, PTEN, and KLF9 proteins in tumor glandular epithelial (GE) and stromal (ST) cells. The percentages of immunopositive cells for PGR and for KLF9 in GE and for PTEN in ST were higher while those for ERα in GE but not ST were lower, in tumors of MET vs. CON patients. The numbers of Ki67- and TUNEL-positive cells in tumor GE and ST did not differ between groups. In human Ishikawa endometrial cancer cells, MET treatment (60 μM) decreased cell numbers and elicited distinct temporal changes in ESR1, KLF9, PGR, PGR-B, KLF4, DKK1, and other tumor biomarker mRNA levels. In the context of reduced KLF9 expression (by siRNA targeting), MET rapidly amplified PGR, PGR-B, and KLF4 transcript levels. Our findings suggest that MET acts directly in EC cells to modify steroid receptor expression and signaling network and may constitute a preventative strategy against EC in high-risk non-diabetic women.

The Human Myometrial Transcriptome and the DNA Methylome of Testosterone-treated Patients Resemble the Myometria from Fibroid Patients

Abstract Uterine fibroids, or leiomyomas, are noncancerous tumors of the myometrium and the most common tumors in women, with a cumulative incidence of approximately 80% by age 50. Currently, hysterectomy is the only definitive cure, and effective non-hormonal therapeutics are lacking. Understanding the etiology of fibroids may lead to alternative, less invasive treatments. Several obstetric disorders, including polycystic ovary syndrome (PCOS), have been linked to uterine fibroids, and women with PCOS often exhibit hormonal imbalances, particularly elevated serum testosterone levels. However, the impact of testosterone on the myometrium remains poorly understood. We hypothesize that elevated testosterone may increase the risk of developing uterine fibroids. Using RNA sequencing and MethylationEPIC array analyses, we compared myometrial tissue from women without fibroids (MyoN, n = 33), with fibroids (MyoF, n = 66), and after testosterone therapy as part of clinical care for gender dysphoria (MyoT, n = 7). The transcriptomic and methylation profiles of MyoT clustered with MyoF and were distinct from MyoN. We identified 1,321 differentially expressed protein-coding genes between MyoT and MyoN, while only 494 were found between MyoT and MyoF. Disease ontology analysis of MyoT vs. MyoN revealed enrichment of the fibroid tumor gene set. Fibroid associated genes including TGFβ3, CCND1, SERPINE1, and FGFR1 were upregulated in MyoT and MyoF samples compared to MyoN samples. The DNA methylation profiles of MyoT were closer to those of MyoF, but no correlation was observed between methylation status and gene expression. Our preliminary data suggest that exogenous testosterone induces transcriptional and methylation changes in the myometrium consistent with those observed in MyoF tissues. These findings suggest that elevated testosterone may be associated with an increased risk of developing uterine fibroids.

Circular RNA-ITCH Inhibits the Proliferation of Ovarian Carcinoma by Downregulating lncRNA HULC

Circular RNA-ITCH has been proven to be tumor suppressor in esophageal and lung cancer, while the role of this RNA in other types of cancers is unknown. In this study, we observed that circular RNA-ITCH was downregulated, while lncRNA HULC was upregulated in ovarian carcinoma. Circular RNA-ITCH and HULC were inversely and significantly correlated. Overexpression of circular RNA-ITCH resulted in inhibited, while overexpression of HULC promoted the proliferation of cells of ovarian cancer cell lines. Overexpression of circular RNA-ITCH led to inhibited HULC in cells of ovarian cancer cell lines, while overexpression of HULC failed to significantly affect the expression of circular RNA-ITCH but attenuated the inhibitory effects of circular RNA-ITCH overexpression. However, overexpression of circular RNA-ITCH failed to affect cancer cell behaviors. Therefore, circular RNA-ITCH may inhibit the proliferation of ovarian carcinoma by downregulating HULC.

Progress in High Intensity Focused Ultrasound Ablation for Fertility Preservation Therapy of Uterine Fibroids and Adenomyosis

Abstract High intensity focused ultrasound (HIFU) is an effective and safe non-invasive treatment method, widely used in the treatment of uterine fibroids and adenomyosis in the field of gynecology. The side effects in HIFU is low in incidence and mild. HIFU can significantly alleviate the symptoms of patients, reduce lesion volumes, improve quality of life, and has good cost-effectiveness. HIFU can accurately ablate the uterine fibroids and adenomyosis lesions, without destroying normal myometrium and endometrium, and thus HIFU is a promising alternative to myomectomy in uterine fibroids patients with fertility desire. Several studies have shown that in terms of ovarian endocrine function protection, HIFU treatment is superior to uterine artery embolization, and similar to myomectomy. Existing limited researches show that patients with uterine fibroids have a favorable pregnancy rate and live birth rate, as well as a lower natural abortion rate after HIFU treatment. Pregnancy rate after HIFU treatment for uterine fibroids is not lower than myomectomy, and higher than uterine artery embolization. HIFU may have significant advantages in shortening pregnancy interval compared with myomectomy. However, the proportion of cesarean section delivery after HIFU treatment is relatively high, and gestational uterine rupture after HIFU treatment exist in literature. Higher quality clinical data is needed to confirm the pregnancy outcomes and safety after HIFU treatment in future.

The Annual Economic Burden of Uterine Fibroids in the United States (2010 Versus 2022): A Comparative Cost-Analysis

In 2010, the estimated annual cost of uterine fibroids in the United States ranged from 5.9 to 34.4 billion USD. In the past decade, more uterine-sparing and fertility preserving interventions have become available to treat symptomatic fibroids. This comparative cost-analysis aims to evaluate change in societal costs of uterine fibroids in the US between 2010 and 2022 given changing fibroid and obstetric management, population growth, and inflation. A systematic review was conducted to update uterine fibroid, treatment, and obstetric complication prevalence, direct costs of medical and surgical interventions, indirect productivity costs, and obstetric costs attributable to fibroids in 2022. A comparative cost-analysis with paired t-tests was performed using baseline data published in 2010. Percent (%) changes between 2010 and 2022 were reported. NIH research funding for fibroids and other common diseases was compared. All costs were converted to 2023 USD. The number of US women with uterine fibroids increased by 10.6% from 2010 to 2022. Over this period, the economic burden of uterine fibroids increased up to 41.4 billion USD compared to 34.4 billion USD in 2010. Overall costs increased to 42.2 billion USD after incorporating new costs associated with MRgFUS and infertility. Direct costs of medical management decreased while costs of surgical interventions increased as a result of evolving treatment-seeking behavior. Lost work costs continue to account for the largest proportion of the economic burden for fibroids. Cesarean section delivery remains the largest contributor (average 80.0%) to indirect obstetrical costs. Despite the rise in the number of individuals affected by uterine fibroids and its sizable annual cost to society, uterine fibroids research continues to be underfunded.

Immunohistochemical Analysis of GATA2 Expression in Endometrium and its Relationship with Hormone Receptor Expression in Benign and Premalignant Endometrial Disorders

AbstractThe GATA gene family encodes highly conserved zinc-finger transcription factors that facilitate the development and function of multiple organ systems including the uterus. In the endometrium, GATA2 functions in a positive autoregulatory loop with the progesterone receptor (PGR) and colocalizes with PGR on chromatin to promote PGR transcriptional programs. GATA2 also has PGR-independent functions that maintain endometrial cell identity, and GATA2 transcripts reportedly are down-regulated in endometrial disorders including endometriosis. This event is accompanied by a reciprocal increase in GATA6. Here, we applied custom anti-GATA2 monoclonal antibodies and performed GATA2 immunohistochemistry (IHC) on patient endometrial tissues corresponding to proliferative, secretory, inactive, and hormone-treated endometrium, as well as endometriosis and endometrial atypical hyperplasia/endometrioid intraepithelial neoplasia (EAH/EIN). We also performed IHC for the estrogen receptor, PGR, and GATA6 in relevant groups. The results reveal a tight correlation between GATA2 and PGR expression in the glandular and stromal cells of benign endometrium. GATA2 expression is markedly reduced in stromal but not glandular cells in endometriosis and EAH/EIN. This reduction in GATA2 expression does not lead to a detectable increase in GATA6 expression in endometriosis. Although average glandular GATA2 expression was preserved in endometriosis and EAH/EIN cases, its expression was decoupled from PGR, implying that alternative pathways regulate GATA2 levels in these disorders. Our findings indicate that GATA2 dysregulation is a feature of endometriosis and EAH/EIN, and support a model whereby loss of stromal GATA2 in these disorders contributes to their progesterone insensitivity.

Super-Enhancer-Driven RAE1 Shows Higher Protein Levels in Tumor Compared to Adjacent Nonmalignant Stroma in High-Grade Serous Ovarian Cancer Patients

Tertiary Lymphoid Structures Are Associated with a Favorable Prognosis in High-Grade Serous Ovarian Cancer Patients

There was accumulating evidence indicating that tertiary lymphoid structures (TLSs) were strongly associated with improved survival and clinical outcome in several solid tumors. In this study, we intended to assess the presence of TLSs and their potential clinical significance in high-grade serous ovarian cancer (HGSOC). TCGA (The Cancer Genome Atlas) cohort included RNA-seq data of 376 HGSOC patients, of which 74 patients included available hematoxylin-eosin (H&E) sections; GEO (Gene Expression Omnibus) cohort, GSE140082, included microarray data of 212 HGSOC patients. TLSs were counted by pathological sections, and the relative abundance of TLSs was assessed by the unsupervised consensus clustering of 12-chemokine transcriptome signatures. The potential associations between TLSs and clinical prognosis, tumor microenvironment (TME), and immunotherapy response of HGSOC were further performed based on transcriptome data. In the H&E sections of HGSOC, TLSs were predominantly located in the stroma and invasive margin of the tumor. Pathological counting results suggested that the expression of 12 chemokines was significantly higher in samples abundant with TLSs than that in the lack of TLSs. Consensus clustering of both TCGA and GEO cohorts divided HGSOC patients into two clusters with different TLSs abundance: low- and high-TLSs. Based on transcriptome analysis, the high-TLS cluster was characterized by better clinical prognosis, a higher degree of immune infiltration, more biological pathways, higher tumor mutational burden score, and higher expression of immune checkpoints. In conclusion, TLSs strongly correlated with the immune-responsive microenvironment and remained a favorable prognostic factor independent of other clinical characteristics in HGSOC. The presence of TLSs was also associated with a potentially favorable response to immune checkpoint blockade (ICB) therapy in HGSOC.

Effect of GLIS1 on the Lymph Node Metastasis of Cervical Squamous Carcinoma Based on Transcriptome Analysis

Cervical cancer remains the leading cause of cancer-related mortality among female reproductive malignancies, and lymph node metastasis (LNM) represents the major reason for its poor prognosis. In this study, we aimed to identify transcriptome differences in patients with cervical squamous cell carcinoma (CSCC) who developed LNM or not and to outline the function of GLIS1 in determining metastatic fate in CSCC. In The Cancer Genome Atlas-endocervical adenocarcinoma project, patients with LNM had shorter overall survival than those without. Transcriptome data from CSCC patients with and without LNM were analyzed to screen for differentially expressed genes (DEGs). DEGs were enriched in metastasis-related pathways, such as extracellular matrix organization, cell-cell adhesion, and regulation of tissue remodeling. GLIS1 was overexpressed in tumor tissues of patients with LNM. COMP and ITGA11 were screened as downstream targets of GLIS1. GLIS1 promoted their transcription by binding to the promoter regions of COMP and ITGA11. GLIS1 enhanced the migration, invasion, and epithelial-mesenchymal transition in CSCC cells, while the knockdown of COMP or ITGA11 reversed the promotion of GLIS1 on CSCC cell malignant phenotype. Together, our results demonstrate that GLIS1 might be related to the LNM of CSCC patients via COMP and ITGA11.

Long Non-coding RNA FOXD2-AS1 Silencing Inhibits Malignant Behaviors of Ovarian Cancer Cells Via miR-324-3p/SOX4 Signaling Axis

It is urgent to develop new therapeutic strategies for ovarian cancer (OC). Long-noncoding RNAs (lncRNAs) have participated in multiple biological processes including tumor recurrence and progression. This study aimed to determine the effects and potential regulatory mechanism of lncRNA FOXD2-AS1 in OC progression. Levels of lncRNA FOXD2-AS1 and miR-324-3p in OC tissues and cell lines were analyzed using quantitative real-time PCR (qRT-PCR). The direct target between FOXD2-AS1 or miR-324-3p was determined using bioinformatics tools and further verified by dual-luciferase reporter assay. Cell viability, apoptosis, migration, along invasion were assessed by MTT, flow cytometry, as well as Transwell assays, respectively. In addition, the levels of miR-324-3p, PCNA, MMP9, Bax, Bcl-2, and SOX4 in OC cells were evaluated using qRT-PCR and western blot assays. We observed that lncRNA FOXD2-AS1 was up-regulated while miR-324-3p was down-regulated in OC tissues and cell lines, especially in SKOV3 cells. Moreover, miR-324-3p was a direct target of lncRNA FOXD2-AS1. Meanwhile, SOX4 interacted with miR-324-3p and was negatively regulated by miR-324-3p in SKOV3 cells. Function assays confirmed that lncRNA FOXD2-AS1 silenced depressed cell proliferation, migration, and invasion while accelerating apoptosis. These functions of lncRNA FOXD2-AS1 were attenuated by miR-324-3p inhibition. Our research demonstrated that FOXD2-AS1 silencing restrained cell growth and metastasis of OC via regulating miR-324-3p/SOX4 axis, indicating that lncRNA FOXD2-AS1 could be a novel potential therapeutic target for OC.

Down-regulation of FA-BRCA Pathway in Cervical Carcinoma Gradually Reversed During the Development of Chemo-tolerance: Clinical Implications

Cervical cancer is one of the leading causes of cancer death among females, worldwide. The contributory role of different cellular pathways in the process of carcinogenesis is still poorly understood. Our study was focused here to understand the functional evaluation of key regulatory genes of FA-BRCA pathway in the development of CACX and their role in chemo-tolerance of the disease by analyzing the molecular profile of the genes both in normal and tumour tissue of our sample pool, also validated in in silico datasets. Later on, prognostic importance of the genes was further evaluated in plasma DNA and cisplatin-treated in vitro system. We found that expression profile of FA-BRCA pathway genes was gradually reduced from undifferentiated basal-parabasal layers of normal tissue towards the progression of the disease. Further analysis revealed that frequent promoter methylation [32-55%] and deletion [34-52%] events were the plausible reasons for their reduced expression in CACX. Noticeably, invasion of promoter methylation of the genes [11-17%] in plasma CTCs of CACX patients was positively correlated [p < 0.001] with poor prognosis among patients. On the other hand, functional upregulation of these genes at higher concentrations [IC50-70] of cisplatin was a predictor for the development of drug tolerance, as evaluated in our in vitro study. This finding was supported further by low prevalence of γ-H2X foci formation and reduced expression of DNMT1 at higher concentrations of cisplatin. In totality, we discovered that the FA-BRCA pathway must be inactivated for cancer formation. In contrast, elevated gene expression played a substantial role in building of chemo-tolerance and might be associated with developing increased risk of disease recurrence among patients.

Atypical Placental Site Nodules within the Diverticulum of the Uterine Incision, a Rare Gestational Trophoblastic Disease Misdiagnosed as Intrauterine Residue: A Case Report

AbstractAtypical placental site nodule (APSN) is a rare benign gestational trophoblastic disease (GTD). It is a tumor-like transformation that has a certain probability of developing into a placental site trophoblastic tumor (PSTT) or epithelioid trophoblastic tumor (ETT). Because of its atypical clinical presentation, it is difficult to diagnose and susceptible to misdiagnosis highly, thus delaying the patient’s condition. We report a scarce case of atypical nodules at the placental site of the uterine incision diverticulum in a 35-year-old female, who was irregular vaginal bleeding after a cesarean Sect. 2 years. She was diagnosed by several local hospitals with intrauterine residue and was given a variety of Traditional Chinese Medicine (TCM) orally, but the symptoms of irregular vaginal bleeding have not been alleviated. After being transferred to several hospitals, she went to Hubei Maternal and Child Health Hospital for treatment. Under the condition of excluding the second pregnancy, she underwent hysteroscopic resection of lesions and laparoscopic repair of uterine incision diverticulum. The pathological diagnosis after the operation suggested that the focus at the uterine incision was an atypical placental nodule that invaded the myometrium of the uterus. The operation completely removed the focus, and then the patient was followed up every 3 months in the first postoperative year, then every 6 months up to 3 years, and then annually thereafter up to 5 years, and then maybe every 2 years thereafter. The patient’s condition was quickly controlled, and the prognosis was good.

A Novel Eight-Gene Signature for Lipid Metabolism Predicts the Progression of Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma

Recently, studies on the mechanisms underlying lipid metabolic reprogramming in cancer have increased. However, its significance in cervical cancer remains unclear. In the present study, a prognostic signature was constructed for patients with cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) using the expression profiles of lipid metabolism-related genes (LMRGs). Furthermore, using various bioinformatics methods, a prognostic gene signature was developed for progression-free survival (PFS). This signature was externally validated using a cervical cancer dataset (GSE44001). The characteristics of the molecular subgroups of LMRGs were analyzed, and target LMRGs were identified via differential gene analysis of the expression profiles and weighted gene correlation network analysis. Thereafter, the identified target genes were used to develop the prognostic gene signature using univariate, least absolute shrinkage and selection operator, and multivariate Cox regression analyses. The performance of the LMRG signature was evaluated using Kaplan-Meier curves, time-dependent receiver operating characteristic curves, decision curve analysis, mutation landscapes, gene set enrichment analysis, and immune score calculation. As a result, a novel eight-LMRG signature comprising ALDH3B2, CERS3, FA2H, GLTP, NR1H3, PLIN3, SLC44A3, and SQLE was constructed. Using this gene signature, patients with CESC and significantly distinguished PFS were divided. This eight-LMRG signature exhibited independent prognostic potential and superior predictive performance compared with a previously developed 12-gene signature. Our findings suggest that our novel eight-LMRG signature contributes to the implementation of precision medicine strategies for managing patients with cervical cancer by facilitating CESC prognosis.

A Metastasis of Ovarian Cancer in the Bartholin Gland: A Case Report with Systematic Literature Review

AbstractThe metastasis of a gynecological malignancy to the Bartholin gland is rare. We report the case of a 62-year-old patient who had undergone extensive treatment of metastatic ovarian cancer that involved the liver, spleen, and peritoneum. She presented with painful swelling of the left vulva. Clinical and sonographic examinations showed a solid tumor in loco typico of the Bartholin gland. Surgical excision was performed. The patient died 3 months after the diagnosis of this metastasis. We performed a systematic search of PubMed, which yielded 453 entries. We selected those with at least an abstract available in English that described metastatic lesions on the Bartholin gland (n = 5). The review showed that a variety of primary cancers (colorectal, medullary thyroid, breast cancer, and endometrial cancers) metastasize to this location. Some patients showed signs of visceral metastasis. Bartholin gland metastases appeared as initial and metachronous manifestations. Most patients were symptomatic, with painful swelling or abscess. Genetic alterations were mentioned in some cases. The main pathways of metastasis discussed were lymphatic, but the mechanism of such metastasis remains unclear. Surgical resection was the preferred treatment option. The literature review indicated that Bartholin gland metastasis of ovarian cancer is rare and associated with poor prognosis. Oncological reasons for vulvar pathologies should be taken into consideration in patients with metastases.

Multi-omics Analysis Identifies Hypoxia Subtypes and S100A2 as an Immunosuppressive Factor in Cervical Cancer

Cervical cancer is a common gynecological oncology. Growing evidence indicates hypoxia plays an important role in tumor progression and immunity. However, no study has examined the hypoxia landscape in cervical cancer. In this study, using hierarchical clustering, we identified three hypoxia subtypes in cervical cancer samples from The Cancer Genome Atlas dataset according to formerly described hypoxia-related genes. The overall survival time, hypoxic features, genomics, and immunological characteristics of these subtypes existed distinct differences. We also created a hypoxia score by principle component analysis for dimension reduction. The hypoxiaScore was an effective prognostic biomarker validated by GSE44001 and was associated with immunotherapy response. Furthermore, combined with single-cell RNA-sequence (scRNA-seq) and experiments, S100A2 was identified as an immunosuppressive factor induced by hypoxia and regulated expression of PD-L1. S100A2 also served as an oncogene promoting the proliferation and migration of cervical cancer cells. These findings depicted a new hypoxia-based classification and identified S100A2 as a potential therapeutic target for cervical cancer, thereby advancing the understanding of immunotherapy resistance mechanisms and cervical cancer genetic markers.

Alternative splicing variants involved in pyroptosis and cuproptosis contribute to phenotypic remodeling of the tumor microenvironment in cervical cancer

Cervical cancer (CC) remains a prevalent gynecological malignancy, posing a significant health burden among women worldwide. With the remarkable discoveries of cellular pyroptosis and cuproptosis, there has been a growing focus on exploring the intricate relationship between these two forms of cell death and their impact on tumor progression. In recent years, alternative splicing has emerged as a significant field in cancer research. Thus, the integration of alternative splicing, pyroptosis, and cuproptosis holds immense value in studying their collective impact on the occurrence and progression of cervical cancer. In this study, alternative splicing data of pyroptosis- and cuproptosis-associated genes were integrated with public databases, including TCGA, to establish a prognostic model for cervical cancer based on COX regression modeling. Subsequently, the tumor microenvironment (TME) phenotypes in the high-risk and low-risk patient groups were characterized through a comprehensive bioinformatics analysis. The findings of this study revealed that the low-risk group exhibited a predominant immune-active TME phenotype, while the high-risk group displayed a tumor-favoring metabolic phenotype. These results indicate that the alternative splicing of pyroptosis- and cuproptosis-associated genes plays a pivotal role in remodeling the phenotypic landscape of the cervical cancer TME by modulating immune responses and metabolic pathways. This study provides valuable insights into the interplay between alternative splicing variants involved in pyroptosis and cuproptosis and the TME, contributing to a deeper understanding of cervical cancer pathogenesis and potential therapeutic avenues.

DNA Methylation in Ovarian Tumors—a Comparison Between Fresh Tissue and FFPE Samples

AbstractAmong women, ovarian cancer (OC) is one of the most severe forms of malignancy, accounting for a low 5-year survival rate, of approximately 52%. Early symptoms are unspecific and hence hard to detect. The origin of OC and its subtypes are still unclear, underlying the need for efficient diagnostic biomarkers. In that regard, epigenetics studies are emerging in cancer diagnostics, with encouraging outcomes. Among them, DNA methylation profiling has shown that the origins of the cancer epigenome are associated with molecular factors that are crucial to carcinogenesis, such as regulation of oncogenes and tumor suppressors. Furthermore, those events have been detected in abnormal cell morphology before neoplastic formation, indicating its potential crucial use in the OC diagnostics in the future. Nonetheless, studies are limited, and whether methylation analysis can be performed optimally in formalin-fixed paraffin-embedded (FFPE) preparations of OC cases is still elusive. In the present report, we investigated the performance of DNA methylation analysis in FFPE samples, compared to their matched fresh frozen tissue in a small cohort of OC samples. We found that the overall DNA methylation profile in FFPE tissue showed high concordance to that found in fresh frozen tissue, and accounting for the small cohort size, the differentially methylated sites found primarily in frozen tissue, compared to benign samples, were also reproducible in FFPE. Overall, by using samples from our current clinical setting of tissue preservation, these preliminary observations might provide insights into the clinical use of FFPE tissues in methylation studies without critically compromising the outcome.

LncRNA BBOX1-AS1 Aggravates the Development of Ovarian Cancer by Sequestering miR-361-3p to Augment PODXL Expression

Ovarian cancer (OC) is a kind of common gynecological malignancy around the world. Mounting literatures have confirmed the implication of lncRNAs in the development of various cancers. Long non-coding RNA (LncRNA) BBOX1-AS1 has not been reported in most cancer types including OC. Presently, we aimed at exploring the function and regulatory mechanism of BBOX1-AS1 in OC. As a result, we demonstrated the extremely high BBOX1-AS1 expression in OC tissues and cells. BBOX1-AS1 silence inhibited OC progression by suppressing cell proliferation and promoting cell apoptosis. Importantly, BBOX1-AS1 was verified to bind to miR-361-3p, which presented a low expression trend in OC cells. Subsequently, PODXL was testified as the downstream target of miR-361-3p. Of note, BBOX1-AS1 positively regulated PODXL through their competition in binding with miR-361-3p. Furthermore, miR-361-3p inhibition facilitated the growth of BBOX1-AS1-deficient OC cells, while such facilitating effect was then counteracted in response to PODXL depletion. All the results above explained that BBOX1-AS1 was overexpressed in OC and that BBOX1-AS1 caused carcinogenic influences on OC cell growth via miR-361-3p/PODXL pathway, highlighting BBOX1-AS1 as a novel potential target for OC treatment.

NFAT Overexpression Correlates with CA72-4 and Poor Prognosis of Ovarian Clear-Cell Carcinoma Subtype

Current biomarkers did not overcome the limitations of clinical application due to the heterogeneity of ovarian tumors. The role of nuclear factor of activated T cells (NFAT) in the prognosis of different histological subtypes of ovarian cancer remains unclear. NFAT expression was analyzed in 302 ovarian tumors from The Cancer Genome Atlas (TCGA) dataset and was further confirmed by 88 ovarian tumor specimens, including 30 clear-cell carcinoma, 34 serous carcinoma, and 24 papillary serous cystadenocarcinoma. The correlations between NFAT expression, cancer biomarkers, and clinical characteristics in different subtypes of ovarian tumors were analyzed. ALGGEN PROMO, reporter assay, and NFAT overexpression and knockdown were used to identify chondroadherin (CHAD) as the downstream target of NFAT. NFAT was significantly upregulated only in late-stage clear-cell carcinoma, but not in other two subtypes. NFAT levels were correlated with CA72-4 levels and poor overall survival and disease-free survival (P < 0.05), suggesting that NFAT together with CA72-4 were specific prognostic markers for clear-cell carcinoma. Pathological stage and lymph node metastasis were the prognostic factors affecting serous carcinoma (P < 0.05), while CA-125 was the prognostic factor affecting papillary serous cystadenocarcinoma (P < 0.05). PROMO and reporter assay indicated that CHAD was the downstream target of NFAT. In addition, NFAT overexpression and silencing increased and reduced CHAD expression, respectively. NFAT together with CA72-4 were specific tumor markers for risk assessment of unique clear-cell subtype of ovarian tumors. CHAD was identified as the downstream target gene of NAFT and was associated with poor survival of ovarian cancer.

Binding of Intracellular Myeloperoxidase to αV/β1 Integrin Serves as a Mechanism of Survival in Epithelial Ovarian Cancer

We were the first to report that epithelial ovarian cancer (EOC) cells and tissues express myeloperoxidase (MPO) that is known to play a role in immune surveillance and inflammation by myeloid cells. Additionally, we reported that MPO is colocalized with inducible nitric oxide synthase (iNOS), a key pro-oxidant enzyme, and plays a key role in regulating apoptosis in EOC cells. Whereas myeloid cells express MPO in a dimeric form, intriguingly, here we report the unique expression of only the monomeric form of MPO in EOC cells, tissues, and blood of an ovarian cancer patient. Additionally, we have identified a cell membrane receptor, αV/β1 integrin, that is uniquely expressed by both chemosensitive and chemoresistant EOC cells with significantly higher expression in chemoresistant EOC cells. More importantly, we have demonstrated that monoclonal antibodies against αV/β1 integrin induced cytotoxicity in EOC cells, but not in normal cells, that is also synergistic with conventional chemotherapies. Cytotoxicity of αV/β1 antibodies is due to conformational changes in αV/β1 integrin which prevents monomeric MPO binding to αV/β1 integrin inhibiting the activation of MPO, leading to increased apoptosis. Since normal epithelial cells and macrophages lack monomeric MPO and αV/β1 integrin system, targeting this unique MPO-dependent survival mechanism will selectively eliminate EOC cells and will be the target for developing specific ovarian cancer therapies.

LncRNA PART1 Stimulates the Development of Ovarian Cancer by Up-regulating RACGAP1 and RRM2

Ovarian cancer (OC) is a kind of gynecologic malignancy with a high mortality rate. Long non-coding RNAs (lncRNAs) have been reported to exert regulatory roles in multiple diseases. However, the role of lncRNA prostate androgen-regulated transcript 1 (PART1) has not been investigated in the development of OC. In this study, from RT-qPCR analysis, we discovered that PART1 demonstrated high expression in OC cells. Moreover, data from functional assays manifested that PART1 reduction hindered the proliferative, migratory, and invasive capabilities of OC cells. In vivo uncovered that PART1 knockdown impeded OC tumor growth. Furthermore, from the experimental results of RNA pull down, RIP, and luciferase reporter assays, we discovered that PART1 served as a sponge for microRNA-6884-5p (miR-6884-5p) to modulate the expression of Rac GTPase activating protein 1 (RACGAP1) and ribonucleotide reductase regulatory subunit M2 (RRM2). Finally, rescue assays proved that overexpression of RACGAP1 or RRM2 abrogated the suppressive role of PART1 knockdown on OC cell malignant behaviors. RACGAP1 and RRM2 were also revealed to act as oncogenes in OC cells. In summary, our research verified the PART1/miR-6884-5p/RACGAP1/RRM2 axis in OC cells, which signified that PART1 might act as a novel biomarker in OC.

lncRNA NR2F1-AS1 Regulates miR-17/SIK1 Axis to Suppress the Invasion and Migration of Cervical Squamous Cell Carcinoma Cells

lncRNA NR2F1-AS1 has been reported to be upregulated in hepatocellular carcinoma and plays oncogenic roles. Through the analysis of TCGA dataset, we observed the downregulation of NR2F1-AS1 in cervical squamous cell carcinoma (CSCC). This study was performed to analyze the functionality of NR2F1-AS1 in CSCC. It was observed that NR2F1-AS1 was significantly downregulated in tumor tissues than in paired non-tumor tissues in CSCC patients. Levels of NR2F1-AS1 decreased with increased in clinical stages. NR2F1-AS1 can directly interact with miR-17. Overexpression experiments showed that NR2F1-AS1 and miR-17 have no significant effects on the expression of each other. Interestingly, NR2F1-AS1 overexpression led to the upregulation of SIK1, a target of miR-17. Transwell assay analysis revealed decreased invasion and migration rates of CSCC cells after NR2F1-AS1 and SIK1 overexpression. miR-17 overexpression played an opposite role and reduced the effects of NR2F1-AS1 and SIK1 overexpression. Therefore, NR2F1-AS1 regulates miR-17/SIK1 axis to suppress the invasion and migration of CSCC cells.

Circular RNA Circ-ITCH Inhibits the Malignant Behaviors of Cervical Cancer by microRNA-93-5p/FOXK2 Axis

Growing evidence has been demonstrated that circular RNA circ-ITCH plays an important role in the development of several cancers. However, the role of circ-ITCH in cervical cancer has not been evaluated. The aim of the present study was to investigate the biological function of circ-ITCH in cervical cancer both in vitro and in vivo. Our results showed that circ-ITCH was lowly expressed in both human cervical cancer tissues and cell lines. Overexpression of circ-ITCH in HeLa cells significantly suppressed cell proliferation, migration, and invasion. A xenograft tumor model was established to evaluate the role of circ-ITCH in vivo. The results showed that overexpression of circ-ITCH significantly inhibited tumorigenesis of cervical cancer. Mechanism investigations proved that circ-ITCH executed its tumor suppressive activity through sponging microRNA-93-5p (miR-93-5p) and regulating the expression of forkhead box K2 (FOXK2). These findings suggest that circ-ITCH may be a therapeutic target for the management of cervical cancer.

Utility of Endocervical Sampling at Time of Colposcopy when Referral Cytology Is Low Grade or Better

The utility of endocervical sampling at the time of colposcopic examination after less than high-grade screening Papanicolaou smear is unknown. To address this question, we performed a retrospective review using a colposcopy patient care database maintained at our urban academic medical center. We examined the prevalence of high-grade dysplasia in endocervical samples, the prevalence of high-grade dysplasia in directed cervical biopsies, and the correlations between high-grade endocervical dysplasia and patient factors of age and time to colposcopy. A total of 3026 patient records met inclusion criteria. Mean age at the time of colposcopy was 30 ± 9 years with a range of 21-75 years. The mean time to colposcopy was 96 ± 90 days with a range of 4-1207 days. There was no difference in mean age or days to colposcopy in women who had grade 2 or greater cervical intraepithelial neoplasia on endocervical sampling compared to those who did not. The overall prevalence of high-grade dysplasia in endocervical samples in women with less than high-grade screening Pap results was 5.3%. For all entries, 4.2% (126/3026) had grade 2 or greater cervical intraepithelial neoplasia on endocervical sampling that would not otherwise have been identified. This study demonstrates that endocervical sampling has diagnostic utility in the setting of less than high-grade referral Pap smears. No benefit was demonstrated in patients with normal cytology and high-risk strains of human papillomavirus identified on referral Pap.

BRD7-Mediated miR-3148 Inhibits Progression of Cervical Cancer by Targeting Wnt3a/β-Catenin Pathway

Abnormal expression of miRNAs is closely related to the occurrence and development of tumors, and thus has become the most concerned biomolecule in the field of tumors. But so far, miRNAs that are truly recognized and studied for their function are only a small part, and their mechanism in tumors needs to be further studied. In this study, we identify that miR-3148 is downregulated in the development of cervical cancer. In cervical cancer cells, upregulated miR-3148 inhibits cell proliferation and promotes apoptosis, suggesting that miR-3148 acts as a tumor suppressor gene. Furthermore, we explored the mechanism of miR-3148 in cervical cancer cells from both transcriptional and post-transcriptional levels. Our research reveals that on the one hand, bromodomain containing 7 (BRD7) acts as a transcription factor to up-regulate the expression of miR-3148 at the transcriptional level; on the other hand, miR-3148 targets the 3'UTR of Wnt3a mRNA to inhibit Wnt3a expression at the post-transcriptional level, thereby suppressing Wnt3a/β-catenin signaling pathway and exerting its tumor suppressor role in cervical cancer. In conclusion, our study elucidates the mechanism of BRD7/miR-3148/Wnt3a/β-catenin pathway in cervical cancer and provides a new research direction for targeted therapy of cervical cancer.

LncRNA FAL1 Upregulates SOX4 by Downregulating miR-449a to Promote the Migration and Invasion of Cervical Squamous Cell Carcinoma (CSCC) Cells

This study aimed to investigate the role of lncRNA FAT1 in cervical squamous cell carcinoma (CSCC). We found that FAT1 was upregulated in CSCC tissues. The expression of FAT1 was not affected by clinical stages. High levels of FAT1 predicted poor survival. The expression of miR-449a was inversely correlated with the expression of FAT1. SOX4 mRNA expression was positively correlated with the expression of FAT1 in CSCC tissues. FAT1 over-expression led to an upregulated SOX4 expression and downregulated miR-449a expression. MiR-449a over-expression failed to affect FAT1 expression but downregulated SOX4 expression. FAT1 and SOX4 over-expression led to increased rates of CSCC cell migration and invasion, miR-449a over-expression led to decreased rates of CSCC cell migration and invasion and attenuated the effects of SOX4 over-expression. Therefore, FAL1 can upregulate SOX4 by downregulating miR-449a to promote the migration and invasion of CSCC cells.

Long Noncoding RNA HULC Promoter Polymorphism rs1041279 Is Associated with an Increased Risk of Cervical Squamous Cell Carcinoma

Hepatocellular carcinoma upregulated long noncoding RNA (HULC), identified as an oncogene in cervical cancer, is involved in not only the clinical stage, lymph node metastasis, and depth of cervical invasion but also outcome. In this study, we aimed to investigate the association between 3 polymorphisms (i.e., rs1041279, rs3005167, and rs7770772) in the promoter of HULC and the risk of cervical squamous cell carcinoma (CSCC). The polymorphisms were genotyped using the multiplex ligase detection reaction assay. The promoter activity was measured using the dual-luciferase reporter assay kit. The rs1041279 GG genotype and G allele revealed a significantly higher risk of CSCC compared with the rs1041279 CC genotype and C allele (GG vs. CC, adjusted OR = 1.79, 95% CI, 1.17-2.73, P = 0.007; G vs. C, adjusted OR = 1.36, 95% CI, 1.09-1.69, P = 0.006). Haplotype analysis revealed that the rs3005167C-rs7770772G-rs1041279C or rs3005167C-rs7770772G-rs1041279G haplotype had a significantly higher risk of CSCC compared to the rs3005167G-rs7770772G-rs1041279C haplotype (CGC vs. GGC, OR = 2.38, 95% CI, 1.53-3.75, P < 0.001; CGG vs. GGC, OR = 3.76, 95% CI, 2.12-6.68, P < 0.001). Dual-luciferase reporter assay showed that the rs1041279 G promoter resulted in higher transcriptional activity compared with the rs1041279 C (P < 0.01). Additionally, the rs1041279 GG genotype carriers had an increased level of HULC expression (P = 0.03). These findings suggest that the HULC rs1041279 may be a useful marker for the etiology of CSCC.

A Functional Polymorphism in the Promoter of miR-17-92 is Associated with a Reduced Risk of Cervical Squamous Cell Carcinoma

miR-17-92 cluster was differentially expressed in cervical cancer, playing an important role in regulating cell proliferation, apoptosis, migration, and invasion. The purpose of this study was to investigate the association between polymorphisms (i.e., rs9588884, rs982873, and rs1813389) in the promoter of miR-17-92 and the risk of cervical squamous cell carcinoma (CSCC). The rs9588884 polymorphism was genotyped using a Taqman assay and the rs982873 and rs1813389 polymorphisms were genotyped using a polymerase chain reaction-restriction fragment length polymorphism method. The expression levels of miR-17-92 were determined using a quantitative PCR analysis. The rs9588884 GG genotype was associated with a reduced risk of CSCC in homozygote comparison (adjusted OR = 0.47, 95% CI, 0.30-0.75, P = 0.001), dominant model (adjusted OR = 0.67, 95% CI, 0.50-0.91, P = 0.01), and recessive model (adjusted OR = 0.57, 95% CI, 0.38-0.85, P = 0.01). The rs9588884 G allele was also associated with a reduced risk of CSCC in allele comparison (adjusted OR = 0.71, 95% CI, 0.58-0.88, P = 0.002). Moreover, patients with the rs9588884 GG genotype had lower levels of miR-20a compared with the rs9588884 CC genotype (P = 0.03). These findings indicate that the rs9588884 GG genotype was associated with lower levels of miR-20a and eventually related to the risk of CSCC in Chinese women.

Large Conization—Retrospective Monocentric Results for Fertility Preservation in Young Women with Early Stage Cervical Cancer

Abstract  The shorter cervical segment after classic radical trachelectomy (RT) imposes a number of pregnancy associated risk factors. In this aspect, large conization (LC) could be an oncologically safe alternative to RT in young women with early stage cervical cancer who want to spare their fertility. Our aim was to evaluate fertility-sparing surgical treatment of early stage cervical cancer after the introduction of LC. Our objectives were to assess surgical, oncological, fertility and obstetric outcomes. We retrospectively investigated oncological and fertility outcomes of patients who underwent LC in a large oncological single University centre between 2009 and 2014. Medical records were reviewed and analysed for surgical, oncological, fertility and obstetric outcomes. Postal questionnaires were collected to further evaluate and validate the fertility and obstetric outcomes. A total of 23 LCs were analysed. Seven patients had to undergo secondary radical hysterectomy after LC due to unclear resection margins. Nine of 16 women tried to conceive, of which all nine became pregnant. Seven patients underwent a prophylactic cerclage between 13 and 16 gestational weeks and seven women delivered 9 children; the majority of women conceived spontaneously. Follow-up time was a median of 3.9 years (2.6–8 years). There was no relapse of cervical cancer in the investigated timeframe. Early stage cervical cancers treated by LC are associated with excellent oncological outcomes. LC appears to be a safe option for eligible women who intend to maintain their fertility.

Knockdown of CTMP Enhances Progesterone Sensitivity in Endometrial Cancer by Inhibiting the PI3K/AKT Signaling Pathway

Progesterone resistance is a key factor in the failure of conservative treatment in young endometrial cancer patients, and there is no effective method to predict and reverse progesterone resistance. CTMP is known to be involved in the development and progression of endometrial cancer, but the mechanism is unidentified. In this study, the immunohistochemical method was used to detect the expression of CTMP in the endometrium before and after progesterone treatment. In cell culture experiments, cell growth and proliferation were examined using CCK-8 and EDU incorporation assay. CTMP and PI3K/AKT pathway-related proteins expression were examined using Western blot. The results show that CTMP expression in the progesterone-resistant group of AEH was not significantly different from that in the progestin-sensitive group before treatment. There was no significant change in the expression of CTMP in the AEH progestin-resistant group, whereas there was a significant decrease in the expression of CTMP in the progesterone-sensitive group after treatment. CTMP knockdown enhances the sensitivity of endometrial cancer cells to medroxyprogesterone acetate (MPA) and may act by inhibiting the PI3K/AKT signaling pathway. This study confirms that CTMP may be associated with sensitivity to progestin therapy in endometrial atypical hyperplasia and endometrial cancer. CTMP may induce the development of progesterone resistance in endometrial cancer through activation of the PI3K/AKT signaling pathway.

Circ_0005576 Exerts an Oncogenic Role in Cervical Cancer via miR-1305-Dependent Regulation of PAIP1

AbstractCervical cancer (CC) is a leading cause of high morbidity and mortality in women worldwide. Circular RNAs (circRNAs) are considered to be essential regulators of various cancers, including CC. The purpose of this study was to investigate the role and mechanism of circ_0005576 in CC progression. The levels of circ_0005576, miR-1305, and poly(A)-binding protein-interacting protein 1 (PAIP1) were detected by quantitative real-time PCR (qRT-PCR) or western blot assay. The stability and location of circ_0005576 were determined by ribonuclease R (RNase R) assay and subcellular fractionation distribution assay, respectively. Cell proliferation was evaluated by CCK-8 assay, EDU incorporation assay, and colony formation assay. Cell migration and invasion were assessed by transwell assay. The interactions between miR-1305 and circ_0005576 or PAIP1 were validated by dual-luciferase reporter assay. The protein expression of cyclin D1, vimentin, and matrix metallopeptidase 9 (MMP9) was tested by western blot. Moreover, mice xenograft models were constructed to analyze tumor growth in vivo. Circ_0005576 and PAIP1 were upregulated, while miR-1305 was downregulated in CC tissues and cells. Circ_0005576 was a stable circRNA that was mainly distributed in the cytoplasm of cells. Knockdown of circ_0005576 suppressed the proliferation, migration, and invasion of CC cells, while the silence of miR-1305 facilitated the development of CC cells. Meanwhile, circ_0005576 could sponge miR-1305 to promote PAIP1 expression. Furthermore, PAIP1 overexpression relieved the influence of circ_0005576 silence on the growth of CC cells. Additionally, circ_0005576 silence hindered CC tumor growth in vivo. Circ_0005576 depletion suppressed tumor development in CC by regulating the miR-1305/PAIP1 axis, suggesting that circ_0005576 might be a potential biomarker for CC treatment.