PeerJ

MRS2 and mitochondrial gene networks in endometrial cancer: mechanisms, biomarkers, and therapeutic implications

Magnesium ions and their transport proteins are increasingly recognized for their critical roles in tumor progression. However, their specific mechanisms in endometrial cancer (EC) remain poorly understood. This study investigated the role of Mitochondrial RNA Splicing 2 protein (MRS2), a key mitochondrial magnesium transporter, and its associated genes, in regulating mitochondrial function and the invasive and metastatic capabilities of EC cells. Using a combination of experimental approaches including lactate detection, flow cytometry, immunofluorescence, CCK8 assays, and Transwell migration assays, along with bioinformatics analysis, we investigated the relationship between lactate levels and MRS2 expression in endometrial cancer cells (KLE). Our findings suggest that elevated lactate levels are associated with increased MRS2 expression in mitochondria. This correlation was further linked to enhanced reactive oxygen species (ROS) production and altered expression of mitochondrial-related genes. Notably, MRS2 knockdown resulted in reduced proliferation of KLE cells, supporting a potential functional role of MRS2 in endometrial cancer progression. These findings provide new insights into the molecular mechanisms underlying EC progression and highlight MRS2 as a potential therapeutic target.

TGF-β-mediated activation of fibroblasts in cervical cancer: implications for tumor microenvironment and prognosis

Background Cervical cancer (CC) is a prevalent female malignancy strongly influenced by the tumor microenvironment (TME). This study focuses on the role of TGF-β signaling in cancer-associated fibroblasts (CAFs) and its interaction with immune cells, aiming to elucidate its impact on CC progression. Methods The TME of CC patients was analyzed using scRNA-seq data and we identified the major cell types in the TME with a focus on the activation of the TGF-β signaling pathway in fibroblasts. Gene modules related to the TGF-β signaling pathway were identified by Weighted correlation network analysis (WGCNA). Using The Cancer Genome Atlas Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (TCGA-CESC) dataset, a prognostic gene model was constructed by univariate Cox, LASSO Cox and multivariate Cox regression analyses. For cellular validation, the mRNA level of prognostic model-related genes was tested via quantitative real-time real-time polymerase chain reaction (PCR). Thereafter, the following assays, including cell counting kit-8, scratch and wound healing assays, were applied to assess the viability, migration and invasion of CC cells. Results Analysis at single-cell resolution identified nine major cell types in the TME, and significant activation of the TGF-β signaling pathway in fibroblasts was correlated with tumor proliferation and differentiation. Strong TGF-β signaling communication between fibroblasts and macrophages and NK/T cells suggested a crucial role in the shaping of the immunosuppressive microenvironment. WGCNA analysis identified gene modules significantly associated with the TGF-β signaling pathway. The prognostic model constructed based on three genes, ITGA5, SHF and SNRPN, demonstrated good predictive ability in multiple datasets, validating its potential for clinical application. Meanwhile, the cellular validation assays have revealed the higher expression of ITGA5 and SNRPN and lower expression of SHF in CC cells. Further, ITGA5 knockdown suppressed the viability, migration and invasion of CC cells. Conclusion This study confirmed the important role of the TGF-β signaling pathway in CC, especially in fibroblasts on tumor microenvironment and tumor progression. The current model could effectively evaluate the prognosis of CC, providing a theoretical foundation for developing CC therapies according to the TGF-β signaling pathway. The present results provide new perspectives for further research on the pathological mechanisms and clinical management of CC.

Ferroptosis-related gene transferrin receptor protein 1 expression correlates with the prognosis and tumor immune microenvironment in cervical cancer

Background Ferroptosis is a non-apoptotic iron-dependent form of cell death implicated in various cancer pathologies. However, its precise role in tumor growth and progression of cervical cancer (CC) remains unclear. Transferrin receptor protein 1 (TFRC), a key molecule associated with ferroptosis, has been identified as influencing a broad range of pathological processes in different cancers. However, the prognostic significance of TFRC in CC remains unclear. The present study utilized bioinformatics to explore the significance of the ferroptosis-related gene TFRC in the progression and prognosis of CC. Methods We obtained RNA sequencing data and corresponding clinical information on patients with CC from The Cancer Genome Atlas (TCGA), Genotype Tissue Expression (GTEx) and Gene Expression Omnibus (GEO) databases. Using least absolute shrinkage and selection operator (LASSO) Cox regression, we then generated a multigene signature of five ferroptosis-related genes (FRGs) for the prognostic prediction of CC. We investigated the relationship between TFRC gene expression and immune cell infiltration by employing single-sample GSEA (ssGSEA) analysis. The potential functional role of the TFRC gene was evaluated through gene set enrichment analysis (GSEA). Immunohistochemistry and qPCR was employed to assess TFRC mRNA and protein expression in 33 cases of cervical cancer. Furthermore, the relationship between TFRC mRNA expression and overall survival (OS) was investigated in patients. Results CC samples had significantly higher TFRC gene expression levels than normal tissue samples. Higher TFRC gene expression levels were strongly associated with higher cancer T stages and OS events. The findings of multivariate analyses illustrated that the OS in CC patients with high TFRC expression is shorter than in patients with low TFRC expression. Significant increases were observed in the levels of TFRC mRNA and protein expression in patients diagnosed with CC. Conclusion Increased TFRC expression in CC was associated with disease progression, an unfavorable prognosis, and dysregulated immune cell infiltration. In addition, it highlights ferroptosis as a promising therapeutic target for CC.

MicroRNA-154-5p suppresses cervical carcinoma growth and metastasis by silencing Cullin2 in vitro and in vivo

Background MicroRNA-154-5p (miR-154-5p) plays a role in tumorigenesis in diverse human malignancies. Nevertheless, little is known about the mechanism by which miR-154-5p alters the growth and metastasis of cervical cancer. This research aimed to analyze the role of miR-154-5p in the pathology of cervical cancer in vitro and in vivo. Methods The level of miR-154-5p in human papillomavirus 16 positive cervical cancer cells was examined by real-time quantitative polymerase chain reaction. Bioinformatics predicted the downstream targets and potential functions of miR-154-5p. Furthermore, lentiviral technology was used to construct SiHa cell lines with stable up- and down-expression levels of miR-154-5p. Its differential expression effects on the progress and metastasis of cervical cancer were analyzed using cell culture and animal models. Results MiR-154-5p showed low expression in cervical cancer cells. Overexpression of miR-154-5p could markedly inhibit the proliferation, migration, and colony formation ability of SiHa cells, concomitantly leading to G1 arrest of the cell cycle, while silencing miR-154-5p triggered the opposite results. Meanwhile, overexpression of miR-154-5p restrained the growth and metastasis of cervical cancer by silencing CUL2 in vivo. Additionally, miR-154-5p reduced CUL2 level, and overexpression of CUL2 influenced the effect of miR-154-5p in cervical cancer. In conclusion, miR-154-5p restrained the growth and metastasis of cervical cancer by directly silencing CUL2.

Exploring the potential role of ENPP2 in polycystic ovary syndrome and endometrial cancer through bioinformatic analysis

Background Growing evidence indicates a significant correlation between polycystic ovary syndrome (PCOS) and endometrial carcinoma (EC); nevertheless, the fundamental molecular mechanisms involved continue to be unclear. Methods Initially, differential analysis, the least absolute shrinkage and selection operator (LASSO) regression, and support vector machine-recursive feature elimination (SVM-RFE) algorithms were employed to identify candidate genes associated with ferroptosis in PCOS. Subsequently, the TCGA-UCEC data were utilized to pinpoint the core gene. Then, the expression of ENPP2 in granulosa cells and endometrium of PCOS was validated using real-time PCR (RT-qPCR). Additionally, we investigated the role of ENPP2 in the progression from PCOS to EC through western blotting (WB), colony formation assay, cell scratch assay, transwell assay, and immunofluorescence (IF). Subsequently, ENPP2 gene set enrichment analysis (GSEA) analyses were conducted to identify common pathways involved in PCOS and EC, which were then verified by RT-qPCR. Finally, immune infiltration and the tumor microenvironment (TME) were explored to examine the involvement of ENPP2 in EC progression. Results The datasets TCGA-UCEC (pertaining to EC), GSE34526, GSE137684, and GSE6798 (related to PCOS) were procured and subjected to analysis. The gene ENPP2 has been recognized as the shared element connecting PCOS and EC. Next, we observed a significant downregulation of ENPP2 expression in the granulosa cells in PCOS compared to the normal patients, while an upregulation of ENPP2 expression was observed in the endometrium of hyperandrogenic PCOS patients relative to the normal. In vitro, the WB revealed that 5-dihydrotestosterone (DHT) upregulated ENPP2 expression in Ishikawa and HEC-1-A cells. Additionally, we found that ENPP2 promoted the proliferation, migration, and invasion of Ishikawa and HEC-1-A cells. Subsequently, we discovered that overexpressed ENPP2 may lead to an increase in CYP19A1 (aromatase) and AR mRNA level. IF demonstrated that ENPP2 increased the expression of AR, suggesting a regulatory role for ENPP2 in hormonal response within PCOS and EC. Our findings indicated a significant correlation between ENPP2 expression and the modulation of immune responses.

Adjuvant chemoradiotherapy versus chemotherapy or radiotherapy in advanced endometrial cancer: a systematic review and meta-analysis

Background Endometrial cancer is one of the most common gynecological cancer in the world. However, the available adjuvant therapies, chemotherapy (CT) and radiotherapy (RT), demonstrated several limitations when used alone. Therefore, we conducted a meta-analysis to investigate the clinical effectiveness of chemoradiotherapy (CRT) based on overall survival (OS) and disease-free survival (DFS). Methods A literature search was performed on five databases and one clinical trial registry to obtain all relevant articles. Search for studies was completed on September 9, 2021. A meta-analysis was conducted to determine the overall hazard ratio with the 95% Confidence Interval. Results A total of 17 articles with 23,975 patients in the CRT vs RT group and 50,502 patients in the CRT vs CT group were included. The OS Hazard Ratios (HR) of CRT compared to RT was 0.66 (95% CI [0.59–0.75]; P < 0.00001). Compared to CT, the OS HR was 0.70 (95% CI [0.64–0.78]; P < 0.00001). CRT also significantly improved the DFS compared to CT only (HR 0.79, 95% CI [0.64–0.97]; P = 0.02) However, CRT did not improve the DFS compared to RT only, with HR of 0.71 (95% CI [0.46–1.09]; P = 0.12). Conclusion Adjuvant CRT can significantly improve OS compared to CT or RT alone and improve the DFS compared to CT alone in patients with advanced endometrial cancer. Further research is needed to identify the optimal CRT regimen, and to whom CRT will be most beneficial.

Status of financial toxicity and its influence on quality of life in patients with gynecological malignancies in China

Background Gynecological malignancies impose a substantial health and economic burden in China. The high cost of treatment often results in considerable financial toxicity, placing economic strain on patients and their families. These challenges can reduce treatment adherence, heighten emotional distress, and impair quality of life. This study aims to assess the degree of financial toxicity among patients with gynecological cancers, evaluate its impact on quality of life, and provide evidence to support the development of targeted clinical interventions to mitigate its adverse effects. Methods A convenience sampling approach was employed to recruit 281 patients with gynecological malignancies from two hospitals in Nanjing. A cross-sectional survey was conducted between November 2022 and December 2024. Data were collected using general information questionnaires, the financial toxicity comprehensive scale, and the cancer patient quality-of-life assessment scale. Results Data validity was confirmed using Harman’s single-factor test (first factor explanatory rate was 30.44%). The mean ± SD total financial toxicity score of the patients was 20.80 ±  7.32 points, with 73% (205/281) experiencing significant financial burdens. The financial resource dimension had the lowest mean score 3.40 ± 1.37 points. Multivariate linear regression analysis indicated that the age of children, family per capita monthly income, treatment costs in the past three months, and marital status were the core influencing factors (adjusted R 2 = 0.310). The mean ± SD total quality of life score of the patients was 65.79 ± 11.39 points, and the total financial toxicity score was significantly positively correlated with quality of life ( r = 0.553, P < 0.01). Participants had a mean age of 52.27 ± 10.78 years; cervical cancer accounted for the highest proportion (49.5%); 29.2% were unemployed or had resigned due to illness, and 96.8% reported medical expenses exceeding CNY 5,000 (roughly $701.50) in the past three months. Conclusion The majority of studied patients experienced financial toxicity, with financial status, family dynamics, and widowhood being key influencing factors.

Sialyltransferase-related genes as predictive factors for therapeutic response and prognosis in cervical cancer

Background Cancer-associated hypersialylation is believed to be related to the metastatic cell phenotype and the suppression of sialyltransferases (SiaTs) has been suggested to be a potent preventive strategy against metastasis. The present research discovered SiaTs-related genes for cervical cancer (CC). Methods The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases were applied to obtain the relevant samples. Mutation dataset were processed using mutect2 software. The gene modules were obtained via weighted gene co-expression network analysis (WGCNA), and the enrichment analysis on the genes within the modules was implemented. Cox regression analysis and “glmnet” R package were applied to establish the relevant risk model. “MCPcounter” R package, ESTIMATE algorithm and TIMER online tools were used to depict the tumor immune microenvironment in CC. The mutation landscape was additionally plotted, and the response to immunotherapy in different cohorts were compared. Further reverse-transcription quantitative PCR and Transwell assays were performed to verify the expression and potential function of the screened key genes. Results Mutation of 14 SiaTs was seen in CC. Subsequently, WGCNA-based identification of SiaTs-related gene modules was significantly enriched in metabolism-related pathways. The established RiskScore model manifested excellent prognostic classification efficiency. A poorer prognosis and occurrence of both immune evasion and reduced immunoreactivity may be seen in high-risk patients yet relatively higher immune cell scores were noticeable in low-risk patients. Angiogenesis and MYC target V2 may be the differentially activated pathways in high-risk patients, while those in low-risk patients were KRAS Signaling DN and Interferon alpha response. In addition, most immune checkpoint-correlated genes were identified to express higher in low-risk patients, while higher sensitivities to chemotherapy drugs was discovered in high-risk patients. Cellular assays have revealed that KCNK15, LIF, TCN2, SERPINF2, and CXCL3 were highly expressed yet PIH1D2, DTX1 and GCNT2 were low-expressed in Hela cells and that silencing CXCL3 diminished the number of migrated and invaded Hela cells. Conclusion In this study, we systematically constructed and validated a risk scoring model based on SiaTs-related genes, which can effectively predict the prognosis and potential response to immunotherapy and chemotherapy in CC patients. This provides a new molecular basis and clinical reference for achieving individualized treatment.

Incidence and risk factors of hepatitis E virus infection in women with gynecological tumors in Eastern China

Background Recently, there has been increasing interest in the exploration of the association between the hepatitis E virus (HEV) infection and malignancies; however, epidemiological data for HEV infection among women with a gynecological tumors (GT) are limited. Herein, we investigated the correlation between HEV and GT in Chinese women. Methods We recruited 452 women diagnosed with a primary GT and 452 healthy volunteers to investigate the possible routes and risk factors for HEV infection. The serum antibody levels of anti-HEV IgG and IgM were measured by enzyme-linked immunoassays once a year. Results After a median follow-up time of 5.4 years (range 4 to 7 years), the overall detection rate of anti-HEV antibodies in patients with GT and in controls were 69/452 (15.27%) and 23/452 (5.09%) (P = 0.001), respectively. The seroprevalence of anti-HEV IgG antibodies was significant higher in patients with GT (15.27%) than in healthy controls (5.09%) (P = 0.001). Moreover, 13 (2.88%) patients with GT were positive for IgM antibodies, while only 4 (0.88%) healthy controls tested positive for anti-HEV IgM antibodies (P = 0.028). The highest prevalence of HEV antibodies were detected in patients with ovarian borderline tumors (40%), followed by patients with ovarian cancer (20.54%) and endometrial cancer (18.46%). Multivariable analysis revealed that contact with dogs (OR, 1.88; 95% CI [1.10–3.22]; P = 0.015) and a history of anti-tumor chemotherapy (OR, 1.85; 95% CI [1.07–3.20]; P = 0.028) were independent risk factors for HEV infection. Conclusion Overall, the present study showed that patients with GT are more susceptible to HEV infection in Eastern China, particularly in patients with ovarian borderline tumors. Thus, effective strategies are needed to reduce HEV infection in patients with GT.

Raptor couples mTORC1 and ERK1/2 inhibition by cardamonin with oxidative stress induction in ovarian cancer cells

Background A balance on nutrient supply and redox homeostasis is required for cell survival, and increased antioxidant capacity of cancer cells may lead to chemotherapy failure. Objective To investigate the mechanism of anti-proliferation of cardamonin by inducing oxidative stress in ovarian cancer cells. Methods After 24 h of drug treatment, CCK8 kit and wound healing test were used to detect cell viability and migration ability, respectively, and the ROS levels were detected by flow cytometry. The differential protein expression after cardamonin administration was analyzed by proteomics, and the protein level was detected by Western blotting. Results Cardamonin inhibited the cell growth, which was related to ROS accumulation. Proteomic analysis suggested that MAPK pathway might be involved in cardamonin-induced oxidative stress. Western blotting showed that cardamonin decreased Raptor expression and the activity of mTORC1 and ERK1/2. Same results were observed in Raptor KO cells. Notably, in Raptor KO cells, the effect of cardamonin was weakened. Conclusion Raptor mediated the function of cardamonin on cellular redox homeostasis and cell proliferation through mTORC1 and ERK1/2 pathways.

Knowledge, attitudes and perceptions regarding human papillomavirus among university students in Hail, Saudi Arabia

Background Human papillomavirus (HPV) is a well-known cause of cervical cancer. The prevalence of HPV, insufficient preventive services, inadequate treatment access, socioeconomic conditions, certain cultural causes and values and opinions regarding cervical cancer have been established as factors contributing to the occurrence of cervical cancer in various parts of the world. Objective To determine university students’ knowledge, attitudes and perceptions regarding HPV and its vaccine. Material and Methods The present cross-sectional study included students enrolled at the University of Hail, Saudi Arabia. Data were collected from January to May 2020 using a previously validated 26-item questionnaire. Results A total of 386 participants responded to the survey; the response rate was 80%. The majority of the respondents (63%) were male and 332 (86%) respondents were single among the overall study population. Most respondents were aged 21–25 years (75.6%), followed by 26–30 years (12.7%). In total, 130 (33.7%) respondents reported that they had heard of HPV before, while 174 (45.1%) reported that HPV infections are rare in Saudi Arabia. Furthermore, 102 (26.4%) respondents thought that HPV causes genital warts, while almost 29.5% believed that HPV infection is a sexually transmitted disease. Nearly 76.2% of the respondents did not believe that HPV infection can occur without symptoms. Moreover, 53.4% of the respondents stated that they did not know the health problems associated with HPV infection, while 148 (38.8%) stated that cervical cancer is a health problem associated with HPV infection. When asked about their understanding of the HPV vaccine, nearly 267 (62.2%) respondents believed that there is no vaccine for HPV, while 239 (61.9%) believed that the vaccine does not minimise the risk of cervical cancer. In addition, the respondents reported that they would be far more likely to get an HPV vaccine if recommended by their doctors [relative importance index (RII) = 0.745], followed by their friends (RII = 0.675). Conclusion The present findings provide a clear understanding of university students’ knowledge, perceptions and attitudes regarding HPV; this information can be used to raise awareness by developing an effective educational strategy. However, further research with a larger sample size is recommended; such efforts would also aid in the development of educational services for various age ranges.

Real-world efficacy assessment for sintilimab in recurrent or metastatic cervical cancer

Background Programmed death 1 (PD-1) monoclonal antibodies have been reported as a first-line therapeutic option for recurrent cervical cancer, especially for programmed death ligand 1 (PD-L1)-positive tumors. However, real-world data on the use of PD-1 monoclonal antibodies in patients with an undefined PD-L1 status is scarce. This study analyzed the efficacy and safety of sintilimab in patients with recurrent or metastatic cervical cancer. Methods Data of patients who received sintilimab for the first time in the First Affiliated Hospital of the Army Medical University from November 2019 to July 2022 were collected. The efficacy and safety of sintilimab were evaluated according to Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1) and Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0, respectively. The Kaplan–Meier curve and log-rank test were used to analyze patient survival. Results Twenty-seven (27) patients were included in the study. The median follow-up was 17 (range, 6–40) months. The objective response rate (ORR) and disease control rate (DCR) were 69.6% and 87.0%, respectively, in efficacy-evaluable patients. The ORR of the combination therapy was significantly higher than that of the monotherapy (82.3% vs. 33.3%, P  = 0.045). The ORR was 91.7% for patients who initiated treatment within two months and 37.5% for those who started treatment after two months ( P  = 0.018). In the intention-to-treat population, 55.5% of the patients experienced adverse events, and 14.8% of the patients had grade 3 or higher treatment-related adverse events. Conclusions Sintilimab appeared to demonstrate satisfactory efficacy and safety in the study. The combination therapy showed a higher ORR compared to monotherapy. Furthermore, early initiation of sintilimab as first-line therapy within two months following recurrence is more effective compared to delayed initiation beyond this period in patients with recurrent disease.

Identification and validation of a prognostic model based on immune-related genes in ovarian carcinoma

Background A novel valuable prognostic model has been developed on the basis of immune-related genes (IRGs), which could be used to estimate overall survival (OS) in ovarian cancer (OC) patients in The Cancer Genome Atlas (TCGA) dataset and the International Cancer Genome Consortium (ICGC) dataset. Methods This prognostic model was engineered by employing LASSO regression in training cohort (TCGA dataset). The corresponding growth predictive values of this model for individualized survival was evaluated using survival analysis, receiver operating characteristic curve (ROC curve), and risk curve analysis. Combined with clinical characteristics, a model risk score nomogram for OS was well built. Thereafter, depended on the model risk score, patients were divided into high and low risk subgroups. The survival difference between these subgroups was measured using Kaplan-Meier survival method. In addition, correlations containing pathway enrichment, treatment, immune cell infiltration and the prognostic model were also analyzed. We established the ovarian cancer cell line W038 for this study and identified the performances of GBP1P1 knockdown on a series of activities including cellular proliferation, apoptosis, migration, and invasion of W038 cells in vitro. Results We constructed a 25-genes prognostic model (TNFAIP8L3, PI3, TMEM181, GBP1P1 (LOC400759), STX18, KIF26B, MRPS11, CACNA1C, PACSIN3, GMPR, MANF, PYGB, SNRPA1, ST7L, ZBP1, BMPR1B-DT, STAC2, LINC02585, LYPD6, NSG1, ACOT13, FAM120B, LEFTY1, SULT1A2, FZD3). The areas under the curves (AUC) of 1, 2 and 3 years were 0.806, 0.773 and 0.762, in the TCGA cohort, respectively. Besides, the effectiveness of the model was verified using ICGC testing data. Univariate and multivariate Cox regression analysis exposes the risk score as an independent prognosis predictor for OS both in the TCGA and ICGC cohort. In summary, we utilized comprehensive bioinformatics analysis to build an effective prognostic gene model for OC patients. These bioinformatic results suggested that GBP1P1 could act as a novel biomarker for OC. GBP1P1 knockdown substantially inhibited the proliferation, migration, and invasion of W038 cells in vitro, and increased the percentage of apoptotic W038 cells. Conclusions The analyses of genetic status of patients with 25-genes model might improve the ability to predict the prognosis of patients with OC and help to select patients suit able to therapies. Immune-related gene GBP1P1 might serve as prognostic biomarker for OC.

FGF19 promotes cell autophagy and cisplatin chemoresistance by activating MAPK signaling in ovarian cancer

Background Chemotherapy is one of the primary treatments for ovarian cancer patients. Autophagy has been linked to chemotherapy resistance in tumor cells. Recent studies have suggested that fibroblast growth factor 19 (FGF19) may be involved in the onset and progression of malignancies. However, the relationship between FGF19 and autophagy in ovarian cancer is still unknown. Methods Next-generation sequencing (NGS) was conducted to analyze gene mutation profiles of 62 cases of high grade serous ovarian cancer (HGSOC). Fluorescence in situ hybridization (FISH) was performed to validate the amplification of FGF19 in HGSOC tissues. Quantitative PCR (qPCR) and immunohistochemistry (IHC) were used to analyze the difference of FGF19 in mRNA and protein expression. Meanwhile, bioinformatics techniques were used to analyze the expression profiles of FGF19 and the correlation with prognosis. Besides, immunofluorescence, transmission electron microscopy and Cell Counting Kit 8 (CCK-8) were used to investigate the potential mechanisms. Results In this study, we found that FGF19 promotes cisplatin resistance in ovarian cancer cells by inducing autophagy. NGS analysis of 62 HGSOC cases identified a significantly amplified gene, FGF19. In addition, the expression level of FGF19 in ovarian cancer samples was higher than that in normal samples. FISH results showed a positive correlation between amplification and expression of FGF19. Knockdown of FGF19 inhibited the cell autophagy through decrease in the expression of LC3 and Beclin 1, and increase in the expression of SQSTM1/p62. Furthermore, we observed that p38 MAPK phosphorylation was down-regulated after FGF19 knockdown. IFN-γ, a potential p38 MAPK activator, counteracted the inhibition of cell autophagy and the anti-proliferation effect of cisplatin induced by FGF19 knockdown in ovarian cancer cells. Conclusion FGF19 increases autophagy and chemoresistance in ovarian cancer by activating the p38 MAPK pathway. These results could point to FGF19 being a potential therapeutic target for ovarian cancer.

Study on the mechanism of Danshen-Guizhi drug pair in the treatment of ovarian cancer based on network pharmacology and in vitro experiment

Our study aims to explore the active components and mechanisms of the Danshen-Guizhi drug pair in treating ovarian cancer by network pharmacology and in vitro experiment. The “component-target-pathway” diagram of the Danshen-Guizhi drug pair was established by network pharmacology, and the effective active components, important targets as well as potential mechanisms of the Danshen-Guizhi drug pair were analyzed. The predicted results were verified by molecular docking and in vitro experiments. The main active components of the Danshen-Guizhi drug pair in the treatment of ovarian cancer are salviolone, luteolin, β-sitosterol and tanshinone IIA. The main core target is PTGS2. The pathways involved mainly include the cancer pathway, PI3K-Akt signaling pathway, and IL-17 signaling pathway. The molecular docking results showed that salviolone and tanshinone IIA had good binding ability to the target. The expression of PTGS2 mRNA and PGE2 in ovarian cells were significantly inhibited by salviolone. The mechanism of the Danshen-Guizhi drug pair in the treatment of ovarian cancer may be regulating cell proliferation, apoptosis and tumor immunity. This provides a theoretical basis for the clinical development and application of the Danshen-Guizhi drug pair.

Beyond 2D cell cultures: how 3D models are changing the in vitro study of ovarian cancer and how to make the most of them

3D cell cultures are a fundamental tool in ovarian cancer research that can enable more effective study of the main features of this lethal disease, including the high rates of recurrence and chemoresistance. A clearer, more comprehensive understanding of the biological underpinnings of these phenomena could aid the development of more effective treatments thus improving patient outcomes. Selecting the most appropriate model to investigate the different aspects of cell biology that are relevant to cancer is challenging, especially since the assays available for the study of 3D cultures are not fully established yet. To maximise the usefulness of 3D cell cultures of ovarian cancer, we undertook an in-depth review of the currently available models, taking into consideration the strengths and limitations of each approach and of the assay techniques used to evaluate the results. This integrated analysis provides insight into which model-assay pair is best suited to study different parameters of ovarian cancer biology such as cell proliferation, gene expression or treatment response. We also describe how the combined use of multiple models is likely to be the most effective strategy for the in vitro characterisation of complex behaviours.

A retrospective study of consistency between immunohistochemistry and polymerase chain reaction of microsatellite instability in endometrial cancer

Objectives Identification of endometrial cancers (EC) with mismatch repair deficiency (dMMR) or microsatellite instability-high (MSI-H) is essential for Lynch syndrome screening and treatment stratification. We aimed to assess the utility of immunohistochemistry (IHC) staining for MMR protein expression and polymerase chain reaction (PCR)-based MSI assays in EC and the correlation between MMR/MSI status and various clinicopathological parameters. Methods We reviewed the clinical and pathological information of 333 patients with EC. MMR protein expression was assessed as retained or lost to determine MMR status by IHC staining, and MSI status was identified by PCR capillary electrophoresis (PCR-CE) testing with a National Cancer Institute (NCI) panel. The correlation of MMR/MSI status with clinicopathological features was determined by statistical analysis. Discrepant results were further analyzed using an alternative PCR-CE MSI (Promega panel) method, MLH1 promoter methylation assays, and next-generation sequencing (NGS). Results Among the EC patients, the overall percentage of dMMR was 25.2%, and the overall percentage of MSI-H was 24%. Among the dMMR patients, 50 (59.5%) showed loss of MLH1 and PMS2 expression, 19 (22.6%) loss of MSH2 and MSH6 expression, and seven (8.3%) and eight (9.5%) loss of PMS2 and MSH6 expression, respectively. The dMMR subgroup was significantly younger than the pMMR subgroup, especially for <60-years-old patients (p = 0.038). In addition, we identified a strong correlation between MMR/MSI status and high-grade endometrioid or nonendometrioid components (p = 0.004 or p = 0.003). IHC staining and PCR-CE assay results showed a high level of overall concordance (98.8%, Cohen’s κ = 0.98). Four patients were found to have dMRR/MSS in both examinations. We reanalyzed them with additional methods. One case showed MLH1 promotor methylation, and the other three cases harbored MSH6 germline pathogenic variations. One of the cases with MSH6 deficiency was reanalyzed as MSI-H by alternative PCR-CE assay or NGS testing. Conclusions This study indicates that the combined use of MMR-IHC and PCR-CE MSI analyses may effectively avoid misdiagnoses of EC patients with dMMR/MSI-H. However, use of PCR-CE alone to evaluate MMR/MSI status may lead to missed diagnosis, especially for EC patients with MSH6 deficiency and presenting MSS.

ULK2 suppresses ovarian cancer cell migration and invasion by elevating IGFBP3

Background Ovarian cancer is an aggressive malignancy with high mortality known for its considerable metastatic potential. This study aimed to explore the expression and functional role of Unc-51 like autophagy activating kinase 2 (ULK2) in the progression of ovarian cancer. Methods ULK2 expression patterns in ovarian cancer tissues as well as benign tumor control samples obtained from our institution were evaluated using immunohistochemistry. Cell counting kit 8 and Transwell assays were applied to assess the effects of ULK2 overexpression on cell proliferation, migration and invasion, respectively. RNA sequencing was performed to explore potential mechanisms of action of ULK2 beyond its classical autophagy modulation. Results Our experiments showed significant downregulation of ULK2 in ovarian cancer tissues. Importantly, low expression of ULK2 was markedly correlated with decreased overall survival. In vitro functional studies further demonstrated that overexpression of ULK2 significantly suppressed tumor cell proliferation, migration, and invasion. RNA sequencing analysis revealed a potential regulatory role of ULK2 in the insulin signaling pathway through upregulation of insulin-like growth factor binding protein-3 (IGFBP3) in ovarian cancer cells. Conclusions In summary, the collective data indicated that ULK2 acted as a tumor suppressor in ovarian cancer by upregulating the expression of IGFBP3. Our study underscores the potential utility of ULK2 as a valuable prognostic marker for ovarian cancer.

Circular RNA circMAN1A2 promotes ovarian cancer progression through the microRNA-135a-3p/IL1RAP/TAK1 pathway

Background Ovarian cancer (OC) is the most lethal malignancy in women owing to its diagnosis only at the advanced stage. Elucidation of its molecular pathogenesis may help identify new tumor markers and targets for therapy. Circular RNAs (circRNAs) are stable, conserved, and functional biomolecules that can be used as effective biomarkers for various cancers. Methods In this study, a potential circRNA related to early diagnosis of OC, circMAN1A2, was analyzed. Overexpression/knockdown of circMAN1A2 in OC cells was used to decipher its effects on cell proliferation with a Cell Counting Kit-8, 5-ethynyl-2’-deoxyuridine (EdU), cell cycle, clone formation, and wound healing assay. RNA pull-down and Dual luciferase assay were used to explain the underlying mechanism by which circMAN1A2 regulates OC cell proliferation. In vivo, the effect of circMAN1A2 in OC was evaluated using nude mouse xenograft experiments. Results CircMAN1A2 was highly expressed in OC and promoted proliferation, clone formation, and tumorigenicity of OC cells. In addition, we found that circMAN1A2 acted as a sponge for microRNA (miR)-135a-3p; miR-135a-3p directly targeted the 3’ untranslated region of interleukin 1 receptor accessory protein (IL1RAP) in OC cells, thereby regulating the phosphorylation of transforming growth factor-beta activated kinase 1 (TAK1), which resulted in promotion of OC cell growth. Conclusions CircMAN1A2 promotes OC cell proliferation by inhibiting the miR-135a-3p/IL1RAP/TAK1 axis. In conclusion, circMAN1A2 may be a biomarker for early detection of OC and a target for subsequent therapy.

Sulforaphene suppressed cell proliferation and promoted apoptosis of COV362 cells in endometrioid ovarian cancer

Aim N6-methyladenosine (m6A) RNA methylation exerts a regulatory effect on endometrioid ovarian cancer (EOC), but the specific m6A regulator genes in EOC remain to be explored. This study investigated that sulforaphene (Sul) is implicated in EOC development by regulating methyltransferase-like 3 (METTL3). Methods The dysregulated m6A RNA methylation genes in EOC were determined by methylated RNA immunoprecipitation (MeRIP-seq) and RNA sequencing. The roles of METTL3 and/or Sul on viability, proliferative ability, cell cycle, and apoptosis of EOC cells were determined by MTT, colony formation, flow cytometry, and TUNEL staining assay, respectively. The expression of METTL3 and apoptosis-related proteins in EOC cells was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and western blot assays. Results Five m6A RNA methylation regulators (METTL3, ELF3, IGF2BP2, FTO, and METTL14) were differentially expressed in EOC, among which METTL3 had the highest expression level. Silencing METTL3 reduced the clonal expansion and viability of EOC cells, and caused the cells to arrest in the G0/G1 phase. This also promoted apoptosis in the EOC cells and activated the FAS/FADD and mitochondrial apoptosis pathways. In contrast, overexpressing METTL3 had the opposite effect. Sul, in a dose-dependent manner, reduced the viability of EOC cells but promoted their apoptosis. Sul also increased the levels of IGF2BP2 and FAS, while decreasing the levels of KRT8 and METTL3. Furthermore, Sul was able to reverse the effects of METTL3 overexpression on EOC cells. Conclusions Sul could suppress cell proliferation and promote apoptosis of EOC cells by inhibiting the METTL3 to activate the FAS/FADD and apoptosis-associated pathways.

Prognostic value of lymphocyte-to-monocyte ratio in patients with endometrial cancer: an updated systematic review and meta-analysis

Background Evaluating the risk of metastasis at diagnosis and the likelihood of future recurrence is crucial for the effective management of endometrial cancer (EC). While conventional prognostic indicators hold importance, they often fall short in predicting recurrence, especially in low-risk patients. This study evaluates the prognostic value of the lymphocyte-to-monocyte ratio (LMR) for overall survival (OS), disease-free survival (DFS), and cancer-specific survival (CSS) in EC patients. Methods Eligible studies that provided pretreatment cutoff values of LMR, hazard ratios (HRs), and 95% confidence intervals (CIs) for OS, DFS, CSS, and progression-free survival (PFS) were included in this meta-analysis. Two independent reviewers collected and evaluated the data, and the quality of the included studies was assessed using the Newcastle Ottawa Quality Assessment Scale (NOS). Statistical analyses were performed using STATA software, and subgroup analyses were conducted by race, sample size, and age to assess the consistency of LMR’s prognostic value across different population groups. Results In this meta-analysis, eight studies were included for OS (1,997 patients) and five studies were included for DFS (1,590 patients). LMR was significantly associated with OS (HR 2.29; 95% CI [1.50–3.51]; p = 0.0014), DFS (HR 4.00; 95% CI [1.76–9.07]; p = 0.0094), and CSS (HR, 1.58; 95% CI [1.11–2.25]; p = 0.01). Subgroup analysis indicated that the prognostic value of LMR for OS was consistent across different races, age groups, and sample sizes. However, the correlation between LMR and DFS was influenced by median age, with younger patients (<60 years) showing a stronger association. Sensitivity analyses confirmed the robustness of these results, and Egger’s test showed no significant publication bias. Discussion LMR serves as a valuable prognostic marker for OS, DFS, and CSS in EC patients. Its predictive power remains significant across diverse population groups, underscoring its potential utility in clinical practice. Biological mechanisms linking inflammation and cancer support the role of LMR in prognosis, given the functions of lymphocytes and monocytes in tumor progression and immune response. These findings suggest that incorporating LMR into current prognostic models could enhance risk stratification for EC patients, particularly for identifying those at higher risk of recurrence despite being classified as low risk by traditional systems. In conclusion, LMR is a robust, independent prognostic factor for EC, with significant implications for improving patient management and outcomes through better risk stratification.

Extracellular vesicles in endometrial-related diseases: role, potential and challenges

Endometrial dysfunction underlies many common gynecologic disorders, such as endometriosis, endometrial cancer, intrauterine adhesions, and endometritis, which affect many women around the world. Extracellular vesicles play an important role in the pathophysiologic process of endometrial-related diseases. Extracellular vesicles are released by cells, which usually act as a form of intercellular communication, affecting biological processes such as fibrosis, angiogenesis, cell proliferation, and inflammatory responses by transferring their own proteins, lipids, RNA transcripts, and DNA for messaging, and play a key role in physiological dynamic homeostasis and disease development. This review combines the studies of the last decade, using the sub-description method to introduce the application of different sources of extracellular vesicles in the diagnosis and treatment of related diseases, and discusses the challenges faced by extracellular vesicles in the diagnostic and therapeutic application of endometriosis-related diseases, with the aim of contributing to our understanding of the mechanism of action of extracellular vesicles and their therapeutic roles, so as to provide a reference for the development of endometriosis-related diseases, as well as their prognosis and treatment.

Combination of serum CST1 and HE4 for early diagnosis of endometrial cancer

Purpose Optimal serological biomarkers have been absent for the early diagnosis of endometrial cancer, to date. In this study, we aimed to define the diagnostic performances of individual and combined detection of serum cysteine protease inhibitor 1 (CST1) with traditional tumor markers, including glycated antigen 125 (CA125) and human epididymis protein 4 (HE4), in patients with early-stage endometrial cancer (EC). Methods The performances of individual and combined detection of serum CST1, HE4, and CA125 were evaluated by enzyme-linked immunosorbent assay (ELISA) and chemiluminescent immunoassay, respectively. A training data set of 67 patients with early EC, 67 patients with endometrial benign lesion (EBL), and 67 healthy controls (HC) was used to develop a predictive model for early EC diagnosis, which was validated by an independent validation data set. Results In the training data set, serum CST1 and HE4 levels in the early EC group were significantly higher than in EBL/HC groups (P < 0.05), while there was no significant difference of serum CA125 level between the early EC and EBL/HC groups (P > 0.05). Serum CST1 and HE4 exhibited areas under the curve (AUC) of 0.715 with 31.3% sensitivity at 90.3% specificity, and 0.706 with 23.9% sensitivity at 95.5% specificity, respectively. Combined detection of serum CST1 and HE4 exhibited an AUC of 0.788 with 49.3% sensitivity at 92.5% specificity. The combination of serum CST1 and HE4 showed promise in diagnosis. Conclusion CST1 is a prospective serological biomarker for early EC diagnosis, and the combination of CST1 and HE4 contributes to the further improvement in the diagnosis of patients with early-stage EC.

Clinical value of hemoglobin, albumin, lymphocyte, and platelet indexes in predicting lymph node metastasis and recurrence of endometrial cancer: a retrospective study

Objective To study the clinical importance of hemoglobin, albumin, lymphocyte, and platelet (HALP) indexes in predicting lymph node metastasis and recurrence of endometrial cancer. Methods From July 2016 to July 2020, 158 patients suffering from endometrial cancer who visited the gynecology department of General Hospital of Ningxia Medical University from were collected. Employing the X-Tiles program, the ideal HALP cut-off value was established, and the patients were separated into low and high HALP groups. Univariate and multivariate analysis were used to determine the relationship between HALP score and lymph node metastasis and recurrence of endometrial cancer. Results The optimal cut-off value of HALP score was established to be 22.2 using X-Tiles software, and the patients were separated into high HALP group (HALP score > 22.2, with 43 cases) and low HALP group (HALP score ≤ 22.2, 115 cases). Endometrial cancer patients’ HALP scores were strongly connected with differentiation, the degree of myometrial invasion, and lymph node metastasis (P < 0.05), although not with age, menopausal status, or stage (P > 0.05). Multivariate logistic regression analysis revealed that the HALP score (OR = 2.087) was the influencing factor for lymph node metastasis (P < 0.05). The ROC curve suggested that the AUC of HALP score in predicting lymph node metastasis was 0.871, which had high diagnostic value. When compared to patients without recurrence, HALP scores of patients with recurrence were considerably lower (P < 0.05). Multivariate logistic regression analysis showed that HALP score (OR = 2.216) was the influencing factor for the occurrence of lymph node metastasis (P < 0.05). The ROC curve suggested that the AUC of HALP score in predicting relapse was 0.855, with high diagnostic value. Conclusion The HALP score shows good predictive performance in predicting lymph node metastasis and recurrence of endometrial cancer, and has high clinical value, which helps in improving the accuracy and effectiveness of clinical diagnosis and prognosis research.

Integrative models of histopathological images and multi-omics data predict prognosis in endometrial carcinoma

Objective This study aimed to predict the molecular features of endometrial carcinoma (EC) and the overall survival (OS) of EC patients using histopathological imaging. Methods The patients from The Cancer Genome Atlas (TCGA) were separated into the training set (n = 215) and test set (n = 214) in proportion of 1:1. By analyzing quantitative histological image features and setting up random forest model verified by cross-validation, we constructed prognostic models for OS. The model performance is evaluated with the time-dependent receiver operating characteristics (AUC) over the test set. Results Prognostic models based on histopathological imaging features (HIF) predicted OS in the test set (5-year AUC = 0.803). The performance of combining histopathology and omics transcends that of genomics, transcriptomics, or proteomics alone. Additionally, multi-dimensional omics data, including HIF, genomics, transcriptomics, and proteomics, attained the largest AUCs of 0.866, 0.869, and 0.856 at years 1, 3, and 5, respectively, showcasing the highest discrepancy in survival (HR = 18.347, 95% CI [11.09–25.65], p < 0.001). Conclusions The results of this experiment indicated that the complementary features of HIF could improve the prognostic performance of EC patients. Moreover, the integration of HIF and multi-dimensional omics data might ameliorate survival prediction and risk stratification in clinical practice.

Development and validation of a risk prediction model for overall survival in cervical cancer patients under 50: a prospective cohort study in southwest China

Objective Accurately predicting the prognosis of cervical cancer in younger patients is increasingly important due to the rising incidence of the disease in China and the growing number of cases among individuals under 50. This study aimed to develop a nomogram to predict overall survival (OS) in cervical cancer patients under 50 in southwest China. Methods Clinicopathological and follow-up data for cervical cancer patients under 50 were prospectively collected as part of an ongoing longitudinal cohort study at Chongqing University Cancer Hospital between January 1, 2015, and May 31, 2019. A training cohort ( n  = 703) and a validation cohort ( n  = 301) were randomly selected. Variables associated with OS were assessed using a Cox regression model. Multivariate analysis was used to construct the nomogram and identify independent prognostic factors. The model’s performance was evaluated using decision curve analysis (DCA), calibration curves, area under the receiver operating characteristic curve (AUC-ROC), and the concordance index. Results The final model identified pathology, International Federation of Gynecology and Obstetrics (FIGO) staging, treatment, β2-microglobulin, neutrophil-lymphocyte ratio (NLR), and albumin as independent risk factors for OS in patients under 50. The concordance index for OS was 0.818 in the training cohort and 0.747 in the validation cohort. Calibration curves in both cohorts showed strong agreement between predicted and observed survival probabilities. In the training cohort, AUCs for 1-, 3-, and 5-year OS were 0.851, 0.847, and 0.816, respectively; in the validation cohort, they were 0.810, 0.733, and 0.730. Compared to the FIGO staging system, the nomogram demonstrated superior predictive accuracy and net benefit, as shown by the net reclassification index (NRI) and DCA. Conclusion The nomogram provides a reliable tool for predicting overall survival in cervical cancer patients under 50, supporting more personalized treatment planning.

Retrospective analysis of cervical screening abnormalities in women with type 3 transformation zone without visible lesions

Objective Women with abnormal cervical screening but without visible lesions, particularly those with a type 3 transformation zone (TZ3), present a clinical challenge due to the non-visible squamocolumnar junction, increasing the risk of missed high-grade lesions. There is currently no consensus on optimal follow-up strategies for this group. This study aims to evaluate a risk-based management approach for these patients. Methods A cross-sectional study analyzed data from 4,648 women with TZ3 who underwent colposcopy and endocervical curettage (ECC) with or without cervical biopsies at Hunan Provincial Maternal and Child Health Care Hospital (2021–2024). Logistic regression with restricted cubic splines analyzed demographic, cytological and HPV data to identify HSIL+ predictors and age-risk thresholds. Results Among the study population, 3.1% (145 cases) of HSIL+ were identified despite negative colposcopy, although additional undetected cases may exist. Women with high-grade cytology (ASC-H/HSIL/AGC) had a consistently high HSIL+ risk (32.5%–37.2%) across all HPV subgroups. In low-grade cytology (NILM/ASCUS/LSIL), HPV 16/18 positivity increased HSIL+ risk (2.4%–5.0%) compared to non-HPV 16/18 cases (1.6%–1.8%), with the highest rate observed in LSIL cases (5.0%). In women with low-grade cytology and non-HPV 16/18 positivity, age and HSIL+ risk showed a nonlinear relationship (RCS P-nonlinear = 0.008). Threshold analysis identified 55 years as a critical cutoff, with a 10% annual increase in HSIL+ risk for women ≥ 55. (OR = 1.10, 95% CI [1.02–1.19]; P  = 0.015). Further age-stratified analysis in this subgroup showed a clear upward trend: HSIL+ detection rates were 4.42% in women aged ≥ 65. Conclusion Among women with abnormal cervical screening and no visible lesions at type 3 transformation zone, HSIL+ risk varies by cytology, HPV genotype, and age. Our findings suggest that immediate diagnostic evaluation is warranted for those with high-grade cytology, HPV 16/18 with LSIL, and women aged ≥ 65 years with low-grade cytology and non-16/18 HPV, as their HSIL+ risk exceeds the 4% threshold recommended by current US guidelines. Conversely, women under 65 with low-grade cytology and non-16/18 HPV, or those with NILM/ASCUS and HPV 16/18, may be appropriate candidates for conservative follow-up. These results support a more tailored, risk-based approach to management in this challenging population.

Incidence, persistence, and clearance of cervical human papillomavirus infection among gynecological outpatients in Kunming, Yunnan, China, 2019–2023: a retrospective cohort study

Human papillomavirus (HPV), a leading sexually transmitted pathogen, is characterized by persistent infection, which represents a critical risk factor for cervical carcinogenesis. This retrospective cohort study investigated the epidemiology of HPV among 45,149 gynecological outpatients in Yunnan, China (2019–2023). The 12-month cumulative incidence of HPV infection was 36.84%, with the highest rates observed in the 30–49-year age group. HPV-52 was the predominant subtype, followed by HPV-51, -81, -58, and -16. Persistent infection was observed in 55.56% of cases, most frequently involving HPV-42, -52, -58, -81, and -56, with higher rates in individuals younger than 30 and older than 59 years. Overall clearance reached 74.43% and was inversely correlated with age. Rapid clearance was predominantly observed for HPV-26, -83, -11, -82, and -44, whereas high-risk HPV types (HPV-58, HPV-52, HPV-35) and low-risk types (HPV-42, HPV-81, HPV-43) exhibited prolonged persistence. Regional data indicate elevated risks of incident and persistent infections with HPV-58, HPV-52, HPV-42, and HPV-81, with older populations showing greater susceptibility to persistence and younger individuals demonstrating faster clearance. These findings underscore the age-specific dynamics of HPV infection and highlight priority subtypes for regional cervical cancer prevention strategies.

Establishment and verification of a nomogram model based on the inflammatory indicators of patients with cervical cancer for predicting the risk of their lymph node metastasis

Based on inflammatory indicators, this study aimed to predict the risk of lymph node metastasis (LNM) in patients with cervical squamous cell carcinoma (CSCC) and establish a predictive nomogram model. Methods This retrospective study analyzed the clinical data of 194 patients with stage IA2-IIA2 who underwent surgery at Hebei General Hospital (between January 2017 and August 2023). Patients were divided into two groups based on the presence of LNM or not. Clinical data of the participants were gathered and analyzed to compare the two groups. Logistic regression analysis was used to analyze the factors influencing LNM in patients with CSCC. R software was used to construct a nomogram model to predict LNM in patients with CSCC, and its accuracy was verified. Results Squamous cell carcinoma antigen (SCC-Ag) level, D-dimer level, platelet (PLT) count, and platelet-to-lymphocyte ratio (PLR) index were significantly higher in patients with LNM than in those without LNM (P < 0.05). There was a significant association between lymph vascular space invasion (LVSI) in patients with CSCC and their LNM (P < 0.05). Logistic regression analysis showed that SCC-Ag, PLR, and LVSI in patients with CSCC were independent risk factors for LNM (P < 0.05). A predictive nomogram model was constructed, and the prediction probability was consistent with the actual observed value (Hosmer–Lemeshow P = 0.313). Analyses using the receiver operating characteristic (ROC) curve revealed that the combination of the SCC-Ag, PLR, and LVSI values of patients with CSCC significantly improved the diagnostic efficiency of their LNM (AUC = 0.792, P < 0.001). Conclusion Establishing a nomogram model based on preoperative inflammatory indicators of patients with CSCC can accurately predict the risk of LNM, providing evidence for implementing a clinical diagnosis and treatment scheme.

Barriers to cervical cancer prevention and triage strategies: a study of knowledge, attitudes, and p16/Ki-67 dual-staining utility among high-risk women in Tuoli and Fuyun counties, Xinjiang

Objective To investigate cervical cancer screening knowledge, attitudes, and practices among high-risk women in remote western China, and to identify socioeconomic and systemic barriers influencing screening participation. Additionally, to evaluate the comparative effectiveness of p16 staining versus p16/Ki-67 dual-staining immunocytochemistry in triaging women with cytological abnormalities or HPV-positive results, aiming to reduce unnecessary colposcopy referrals in resource-limited settings. Methods This cross-sectional study enrolled 260 women (aged 20–65 years) with cytological abnormalities or HPV-positive results from two remote counties in Xinjiang Province (January–December 2023). Participants completed structured questionnaires assessing cervical cancer knowledge, screening attitudes, and healthcare access. Cervical specimens collected via liquid-based cytology underwent parallel testing: conventional cytology, p16 staining, and p16/Ki-67 dual-staining, with all analyses performed by blinded pathologists. Results Among 260 high-risk women in Xinjiang, cervical cancer awareness (67.31%, 95% CI [61.50–72.90]) and screening rates (56.15%, 95% CI [50.23–62.17]) remained suboptimal. Multivariable analyses revealed significant disparities: college-educated women had 7.58-fold higher odds of awareness (95% CI [2.32–24.75]) compared to those with primary education, while public servants showed the strongest employment-based association (aOR = 11.23, 95% CI [2.64–47.83]). Mediation analysis demonstrated that health awareness fully mediated the effect of education (128.8% mediation) and nearly fully mediated the effect of employment (93.8%). Notably, 93.98% (95% CI [90.85–96.27]) expressed willingness to rescreen, and 82.95% (95% CI [78.33–86.84]) supported HPV vaccination. Biomarker analysis showed that p16/Ki-67 dual-staining positivity increased progressively with lesion severity (P < 0.001). Conclusion This study reveals suboptimal cervical cancer knowledge and screening rates among women in Xinjiang, with socioeconomic disparities—particularly in education and employment—primarily mediated through health awareness. The findings support integrated interventions, including physician-led education, digital health communication for media-dependent populations, simplified visual materials for less-educated women, and active linkage to national screening programs for unemployed populations. High rescreening willingness and parental acceptance of HPV vaccination indicate strong potential for intervention. p16 staining and p16/Ki-67 dual-staining show promise for triage in resource-limited settings. These findings highlight the need for tailored strategies to enhance cervical cancer prevention in western China, with further research needed to address current limitations.

Preoperative prediction of p16 expression in cervical cancer by amide proton transfer imaging combined with diffusion kurtosis imaging: a retrospective study

Background Immunohistochemical p16 expression is important for the assessment of risk factors and prognosis of cervical cancer. This study evaluated the correlation between preoperative amide proton transfer imaging (APT), diffusion kurtosis imaging (DKI), and p16 expression in cervical cancer. Methods Fifty-five records of patients with cervical cancer with preoperative magnetic resonance imaging (MRI) and complete postoperative pathology were retrospectively analyzed. Uterine MRI scans were examined, and the corresponding APT values, mean kurtosis (MK), and mean diffusivity (MD) were obtained. Pathology was used to determine p16 positivity. The predictive effects of the APT- and DKI-derived parameters applied alone or in combination with p16 expression were compared. Results Among the 55 cases of cervical cancer, 35 were p16 positive and 20 were p16 negative. The receiver operating characteristic curve area (AUC) of p16 was 0.809, 0.801, 0.790, 0.845, 0.866, and 0.871 when APT, MK, and MD were used individually and then jointly. The effect of APT combined with the DKI derivative parameters was more pronounced than when they were used separately. Conclusion Preoperative APT and DKI imaging are valuable in predicting the expression of p16 in cervical cancer, and the combination of the two can improve the prediction efficacy. These findings could help to guide treatment decisions and determine prognosis in cervical cancer.

Upregulation of HPV16E1 and E7 expression and FOXO3a mRNA downregulation in high-grade cervical neoplasia

Background Cervical cancer remains a significant global health concern, ranking as the fourth most prevalent cancer among women worldwide. Human papillomaviruses (HPV) transcribe many genes that might be responsible for cervical cancer development. This study aims to investigate the correlation between the expression of HPV16 early genes and the mRNA expression of human FOXO3a, a tumor suppressor gene, in association with various stages of cervical precancerous lesions. Methods Eighty-five positive HPV16 DNA cervical swab samples were recruited and categorized based on cytology stages, i.e., negative for intraepithelial lesion or malignancy (NILM), atypical squamous cells of undetermined significance (ASC-US), low-grade squamous intraepithelial lesion (LSIL), atypical squamous cell cannot exclude HSIL (ASC-H), high-grade squamous intraepithelial lesion (HSIL). RT-qPCR was performed to amplify HPV16E1, E4, E6, E6*I, E7, and human FOXO3a mRNA expression in all samples. The relative expression of those genes was calculated using GAPDH as a control. Detection of FOXO3a mRNA expression in the cervical cancer cell line by RT-qPCR and meta-analysis of FOXO3a expression using the RNA-Seq dataset by GEPIA2 were analyzed to support the conclusions. Results Among the cervical samples, HPV16E1 and E7 were significantly increased expression correlating to disease severity. HPV16E4 mRNA expression was 100% detected in all LSIL samples, with a significant increase observed from normal to LSIL stages. Conversely, FOXO3a mRNA expression decreased with disease severity, and the lowest expression was observed in HSIL/squamous cell carcinoma (SCC) samples. In addition, similar results of FOXO3a downregulation were also found in the cervical cancer cell line and RNA-Seq dataset of cervical cancer samples. Conclusion HPV16 early mRNA levels, including E1 and E7, increase during cancer progression, and downregulation of FOXO3a mRNA is a characteristic of cervical cancer cells and HSIL/SCC. Additionally, HPV16E4 mRNA expression was consistently detected in all LSIL samples, suggesting the presence of active viral replication. These findings might lead to further investigation into the interplay between HPV gene expression and host cell factors for targeted therapeutic strategies in cervical cancer management.

Identification of 10 differentially expressed genes involved in the tumorigenesis of cervical cancer via next-generation sequencing

Background The incidence and mortality of cervical cancer remain high in female malignant tumors worldwide. There is still a lack of diagnostic and prognostic markers for cervical carcinoma. This study aimed to screen differentially expressed genes (DEGs) between normal and cervical cancer tissues to identify candidate genes for further research. Methods Uterine cervical specimens were resected from our clinical patients after radical hysterectomy. Three patients’ transcriptomic datasets were built by the next generation sequencing (NGS) results. DEGs were selected through the edgeR and DESeq2 packages in the R environment. Functional enrichment analysis, including GO/DisGeNET/KEGG/Reactome enrichment analysis, was performed. Normal and cervical cancer tissue data from the public databases TCGA and GTEx were collected to compare the expression levels of 10 selected DEGs in tumor and normal tissues. ROC curve and survival analysis were performed to compare the diagnostic and prognostic values of each gene. The expression levels of candidate genes were verified in 15 paired clinical specimens via quantitative real-time polymerase chain reaction. Results There were 875 up-regulated and 1,482 down-regulated genes in cervical cancer samples compared with the paired adjacent normal cervical tissues according to the NGS analysis. The top 10 DEGs included APOD, MASP1, ACKR1, C1QTNF7, SFRP4, HSPB6, GSTM5, IGFBP6, F10 and DCN. GO, DisGeNET and Reactome analyses revealed that the DEGs were related to extracellular matrix and angiogenesis which might influence tumorigenesis. KEGG enrichment showed that PI3K-Akt signaling pathway might be involved in cervical cancer tumorigenesis and progression. The expression levels of selected genes were decreased in tumors in both the public database and our experimental clinical specimens. All the candidate genes showed excellent diagnostic value, and the AUC values exceeded 0.90. Additionally, APOD, ACKR1 and SFRP4 expression levels could help predict the prognosis of patients with cervical cancer. Conclusions In this study, we selected the top 10 DEGs which were down-regulated in cervical cancer tissues. All of them had dramatically diagnostic value. APOD, ACKR1 and SFRP4 were associated with the survivals of cervical cancer. C1QTNF7, HSPB6, GSTM5, IGFBP6 and F10 were first reported to be candidate genes of cervical carcinoma.

HPV-driven heterogeneity in cervical cancer: study on the role of epithelial cells and myofibroblasts in the tumor progression based on single-cell RNA sequencing analysis

Background Cervical cancer (CC) is a neoplasia with a high heterogeneity. We aimed to explore the characteristics of tumor microenvironment (TME) for CC treatment. Methods HPV positive (+) and negative (−) samples from cervical cancer (CC) patients were sourced from the Gene Expression Omnibus (GEO) database. The single-cell RNA sequencing (scRNA-seq) data were processed and annotated for cell types utilizing the Seurat package. Following this, the expression levels and biological roles of the marker genes were analyzed applying real-time PCR (RT-PCR) and transwell assays. Furthermore, the enrichment of genes with significantly differential expressions and copy number variations was assessed by the ClusterProlifer and inferCNV software packages. Results Seven main cell clusters were classified based on a total of 12,431 cells. The HPV− CC samples exhibited a higher immune cell infiltration level, while epithelial cells and myofibroblasts had higher proportion in the HPV+ CC samples with extensive heterogeneity. Immune pathways including antigen treatment and presentation, immunoglobulin production and T cell mediated immunity were significantly activated in the HPV− CC group with lower cell cycle and proliferation activity. However, the anti-tumor immunity of these cells was inhibited in HPV+ CC group with higher cell proliferation activity. Moreover, the amplification and loss of CNVs also supported that these cells in HPV− CC samples were prone to anti-tumor activation. Further cell validation results showed that except GZMA, the levels of APOC1, CEACAM6, FOXP3, SFRP4 and TFF3 were all higher in CC cells Hela, and that silencing TFF3 could inhibit the migration and invasion of CC cells in-vitro. Conclusion This study highlighted the critical role of HPV infection in CC progression, providing a novel molecular basis for optimizing the current preventive screening and personalized treatment for the cancer.

Clinical and dosimetric correlation in terms of treatment response, bladder and rectal toxicities in cervical cancer patients treated with cobalt 60 high dose rate brachytherapy

Background High dose rate (HDR) image-guided brachytherapy with Cobalt-60 isotope is a relatively recent approach. The aim of the study is to evaluate the clinical and dosimetric parameters in terms of tumour response, bladder, and rectal toxicity in patients undergoing Co-60 HDR brachytherapy. Materials and Method All patients were initially treated with chemoradiation (CT-RT) at our center or other referral centers with external beam radiation therapy (EBRT) for a dose of 45 Gy–60 Gy at 1.8-2Gy/fraction (including nodal boost) with concomitant chemotherapy with either cisplatin or carboplatin. Patients were then scheduled for brachytherapy within 1 week after completion of CT-RT and are assessed by local examination. Depending on local examination parameters at the time of brachytherapy they were eligible either for intracavitary brachytherapy (ICBT) or interstitial brachytherapy (ISBT). Results The complete response (CR) observed in stage I, II, III, IVA were 60%, 79.4%, 86% and 76.2% respectively. Complete response was seen in patients with mean EQD2 of 78.67 Gy10, 83.33 Gy10, 84.23 Gy10, 85.63 Gy10 in stages I, II, III, IVA respectively. 79.2% of cisplatin-treated patients and 87.5% of carboplatin-treated patients had a complete response indicating that patients treated with either chemotherapy had similar response rates. Conclusions According to results obtained from the study we conclude by saying that higher rates of complete response to treatment in cervical cancer is seen in patients with shorter overall treatment time (OTT), shorter interval between end of definitive CT-RT and beginning of brachytherapy and squamous cell histology. The study also noted the trend of increasing mean EQD2 to tumor with increasing stage for achieving complete response. Higher acute bladder and rectal toxicity is seen in patients who received EQD2 of ¿70-90Gy3 and ¿70Gy3 respectively. The study findings suggest that the clinical outcomes and the toxicities are clinically comparable with other radioisotope based HDR brachytherapy treatment.

Construction and validation of a risk-prediction model for hypovolemic shock after cytoreductive surgery in patients with ovarian cancer: a retrospective study

Introduction Ovarian cancer patients undergoing cytoreductive surgery are prone to hypovolemic shock in the early postoperative period, resulting in tissue hypoperfusion, lactic acid accumulation, endotoxin displacement, and even multiple organ dysfunction syndrome; however, in existing studies, there is a lack of a dynamic approach to assess the risk of postoperative hypovolemic shock. This study aimed to construct and validate a visual prediction model of hypovolemic shock after cytoreductive surgery. Methods This is a retrospective observational study. Patients with ovarian cancer who received cytoreductive surgery at Zhejiang Cancer Hospital between January 2023 and June 2024 were retrospectively enrolled and divided into a training group and a validation group. Independent predictors of hypovolemic shock were identified using least absolute shrinkage and selection operator (LASSO) regression from the training set, and a nomogram was constructed based on these predictors. A nomogram was used to depict the weight of each variable in the logistic regression model on the event occurrence. The performance of the nomogram was assessed using receiver operating characteristic (ROC), calibration curve, and decision curve analysis (DCA). Results A total of 423 patients were eligible for inclusion in this study. There were 301 cases in the training group and 122 cases in the validation group. This visual prediction model was constructed based on the duration of the operation (odds ratio (OR) = 1.273; 95% confidence interval (CI) [1.052–1.552]), the amount of blood lost during the operation (OR = 1.102; 95% CI [1.020–1.196]), the amount of albumin (OR = 0.935; 95% CI [0.879–0.993]) and fibrinogen (OR = 0.606; 95% CI [0.371–0.948]) immediately after the operation, and the postoperative use of sedative drugs (OR = 2.248; 95% CI [1.109–4.538]). The area under the ROC of the nomogram for the training and validation cohorts was 0.800 (95% CI [0.740–0.860]) and 0.821 (95% CI [0.735–0.907]), respectively. The predicted probabilities of the two groups of models were basically consistent with the actual incidence rates, with the average absolute errors being 0.016 and 0.019, respectively. The Hosmer-Lemeshow test of the training group ( P  = 0.722) and the validation group ( P  = 0.565) showed that there was no significant difference between the predicted values and the actual values, indicating that the model fitted well. The results of the DCA curve showed that the two groups had a net benefit within the probability range of risk threshold values of 0.01 to 0.84 and 0.04 to 0.80, respectively. Conclusions The model constructed in this study demonstrates improved predictive accuracy for the risk of hypovolemic shock after cytoreductive surgery in patients with ovarian cancer, and it holds the potential to provide a basis for medical staff to achieve early identification and timely intervention.

Labeled-free quantitative proteomic analysis of cervical squamous cell carcinoma identifies potential protein biomarkers

Background Cervical cancer remains a prevalent cancer among women, and reliance on surgical and radio-chemical therapies can irreversibly affect patients’ life span and quality of life. Thus, early diagnosis and further exploration into the pathogenesis of cervical cancer are crucial. Mass spectrometry technology is widely applied in clinical practice and can be used to further investigate the protein alterations during the onset of cervical cancer. Methods Employing labeled-free quantitative proteomics technology and bioinformatics tools, we analyzed and compared the differential protein expression profiles between normal cervical squamous cell tissues and cervical squamous cell cancer tissues. GEPIA is an online website for analyzing the RNA sequencing expression data of tumor and normal tissue data from the TCGA and the GTEx databases. This approach aided in identifying qualitative and quantitative changes in key proteins related to the progression of cervical cancer. Results Compared to normal samples, a total of 562 differentially expressed proteins were identified in cervical cancer samples, including 340 up-regulated and 222 down-regulated proteins. Gene ontology functional annotation, and KEGG pathway, and enrichment analysis revealed that the differentially expressed proteins mainly participated in metabolic pathways, spliceosomes, regulation of the actin cytoskeleton, and focal adhesion signaling pathways. Specifically, desmoplakin (DSP), protein phosphatase 1, regulatory (inhibitor) subunit 13 like (PPP1R13L) and ANXA8 may be involved in cervical tumorigenesis by inhibiting apoptotic signal transmission. Moreover, we used GEPIA database to validate the expression of DSP, PPP1R13L and ANXA8 in human cancers and normal cervix. Conclusion In this study, we identified 562 differentially expressed proteins, and there were three proteins expressed higher in the cervical cancer tissues. The functions and signaling pathways of these differentially expressed proteins lay a theoretical foundation for elucidating the molecular mechanisms of cervical cancer.

Altered vaginal cervical microbiota diversity contributes to HPV-induced cervical cancer via inflammation regulation

Background Cancer has surpassed infectious diseases and heart ailments, taking the top spot in the disease hierarchy. Cervical cancer is a significant concern for women due to high incidence and mortality rates, linked to the human papillomavirus (HPV). HPV infection leads to precancerous lesions progressing to cervical cancer. The cervix’s external os, near the vagina, hosts various microorganisms. Evidence points to the link between vaginal microbiota and HPV-induced cervical cancer. Cervical cancer onset aligns with an imbalanced Th1/Th2 immune response, but the role of vaginal microbiota in modulating this imbalance is unclear. Methods In this study, we collected vaginal samples from 99 HPV-infected patients across varying degrees of lesions, alongside control groups. These samples underwent bacterial DNA sequencing. Additionally, we employed Elisa kits to quantify the protein expression levels of Th1/Th2 cytokines IL2, IL12, IL5, IL13, and TNFa within the centrifuged supernatant of vaginal-cervical secretions from diverse research subjects. Subsequently, correlation analyses were conducted between inflammatory factors and vaginal microbiota. Results Our findings highlighted a correlation between decreased Lactobacillus and increased Gardenerella presence with HPV-induced cervical cancer. Functionally, our predictive analysis revealed the predominant enrichment of the ABC transporter within the vaginal microbiota of cervical cancer patients. Notably, these microbiota alterations exhibited correlations with the production of Th1/Th2 cytokines, which are intimately tied to tumor immunity. Conclusions This study suggests the potential involvement of vaginal microbiota in the progression of HPV-induced cervical cancer through Th1/Th2 cytokine regulation. This novel insight offers a fresh perspective for early cervical cancer diagnosis and future prevention strategies.

Peripheral blood immune cell parameters in patients with high-grade squamous intraepithelial lesion (HSIL) and cervical cancer and their clinical value: a retrospective study

Objective The objective of this study was to delineate the profile of peripheral blood lymphocytic indices in patients afflicted with high-grade squamous intraepithelial lesions (HSIL) and cervical neoplasms, and to elucidate the correlation of these hematologic markers with the clinicopathological spectra in individuals diagnosed with cervical carcinoma. Methods We adopted a retrospective case-control modality for this investigation. An aggregate of 39 HSIL patients and 42 cervical carcinoma patients, who were treated in our facility from July 2020 to September 2023, were meticulously selected. Each case of cervical malignancy was confirmed through rigorous histopathological scrutiny. Concomitantly, 31 healthy female individuals, who underwent prophylactic health evaluations during the corresponding timeframe, were enlisted as the baseline control group. We systematically gathered and analyzed clinical demographics, as well as the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR), from peripheral blood samples. Pearson’s correlation coefficient was deployed to dissect the interrelation between peripheral NLR and PLR concentrations and the clinicopathological features in the cervical cancer group. Results Inter-group comparative analysis unveiled statistically substantial variances in the PLR and NLR values among the tripartite clusters (F = 36.941, 14.998, P < 0.001, respectively). Although discrepancy in NLR (P = 0.061) and PLR (P = 0.759) measures between the groups of cervical carcinoma and HSIL was not statistically appreciable, these indices were markedly elevated in the cervical carcinoma faction as juxtaposed with the normative control group (t = 5.094, 5.927; P < 0.001 for both parameters). A discernible gradation in peripheral blood PLR and NLR concentrations was noted when stratified by clinical stage and the profundity of myometrial invasion in cervical cancer subjects (P < 0.001). The correlation matrix demonstrated a positive liaison between peripheral blood PLR and the clinical gradation, as well as the invasiveness of the neoplastic cells into the muscularis propria (P < 0.05); a similar trend was observed with the NLR values (P < 0.05). Conclusion Augmented NLR and PLR levels in peripheral blood specimens are indicative of HSIL and cervical malignancy. These hematological parameters exhibit a pronounced interconnection with clinical staging and muscular wall penetration depth, serving as potential discriminative biomarkers for the diagnosis and prognosis of cervical cancer.

Effects of BRD4 inhibitor JQ1 on the expression profile of super-enhancer related lncRNAs and mRNAs in cervical cancer HeLa cells

Objective To investigate the effects of bromine domain protein 4 (BRD4) inhibitor JQ1 on the expression profile of super-enhancer-related lncRNAs (SE-lncRNAs) and mRNAs in cervical cancer (CC) HeLa-cells. Methods The CCK8 method was implemented to detect the inhibitory effect of JQ1 on HeLa cells and explore the best inhibitory concentration. Whole transcriptome sequencing was performed to detect the changes of lncRNAs and mRNAs expression profiles in cells of the JQ1 treatment group and control group, respectively. The differentially expressed SE-lncRNAs were obtained by matching, while the co-expressed mRNAs were obtained by Pearson correlation analysis. Results The inhibitory effect of JQ1 on HeLa cell proliferation increased significantly with increasing concentration and treatment time (P < 0.05). Under the experimental conditions of three concentrations of 0.01, 0.1 and 1 μmol/L of JQ1 on HeLa cells at 24, 48, 72 and 120 h, 1 μmol/L of JQ1 at 72 and 120 h had the same cell viability and the strongest cell proliferation inhibition. In order to understand the inhibitory mechanism of JQ1 on HeLa cells, this study analyzed the expression profile differences from the perspective of SE-lncRNAs and mRNAs. A total of 162 SE-lncRNAs were identified, of which 8 SE-lncRNAs were down-regulated and seven SE-lncRNAs were up-regulated. A total of 418 differentially expressed mRNAs related to SE-lncRNAs were identified, of which 395 mRNAs had positive correlation with 12 SE-lncRNAs and 408 mRNAs had negative correlation with 15 SE-lncRNAs. Conclusion JQ1 can significantly inhibit the proliferation of HeLa cells and affect the expression profile of SE-lncRNAs and mRNAs.

Effects of leptin on the viability of human ovarian cancer cells and changes in cytokine expression levels

Background Obesity is associated with increased mortality among ovarian cancer and is a poor prognostic factor. There are significant links between the leptin hormone, a product of the obesity gene, and the development of ovarian cancer. Leptin is a vital hormone-like cytokine secreted from adipose tissue and is mainly involved in the maintenance of energy homeostasis. It regulates several intracellular signaling pathways and also interacts with various hormones and energy regulators. It acts as a growth factor by stimulating cell proliferation and differentiation and in this way contributes to cancer cell development. The aim of the study was to investigate the effects of leptin on human ovarian cancer cells. Methods In this study, the effects of increasing the concentration of leptin were investigated on the cell viability of OVCAR-3 and MDAH-2774 ovarian cancer lines by MTT assay. Moreover, to elucidate the molecular mechanisms of leptin in ovarian cancer cells, changes in the expression levels of 80 cytokines were evaluated after leptin treatment via a human cytokine antibody array. Results Leptin increases the proliferation of both ovarian cancer cell lines. IL-1 level was increased in OVCAR-3 cells and TGF-β level was increased in MDAH-2774 cells after leptin treatment. A decrease in IL-2, MCP-2/CCL8 and MCP-3/CCL7 levels was detected in both ovarian cancer cell lines with leptin administration. An increase in IL-3 and IL-10 expressions, insulin-like growth factor binding proteins (IGFBP) IGFBP-1, IGFBP-2 and IGFBP-3 levels were detected in both ovarian cancer cell lines with leptin administration. In conclusion; leptin has a proliferative effect on human ovarian cancer cell lines and affects different cytokines in different types of ovarian cancer cells.

Next-generation sequencing shows the genomic features of ovarian clear cell cancer and compares the genetic architectures of high-grade serous ovarian cancer and clear cell carcinoma in ovarian and endometrial tissues

Ovarian clear cell carcinoma (OCCC) is a special histological type of epithelial ovarian cancer (EOC) that is not derived from epithelial cells of the ovarian or fallopian tube as the most common type of ovarian cancer, high-grade serous ovarian carcinoma (HGSOC), but is closely related to endometriosis and similar to endometrial clear cell carcinoma (ECCC) at morphologic and phenotypic features. However, limited data was shown in OCCC genomic features and compared with that in OCCC, HGSOC and ECCC. Herein, we utilized next-generation sequencing analysis of a panel of 1,021 genes to profile the mutational alterations in 34 OCCC and compared them to those from HGSOC (402 cases) and ECCC (30 cases). In result, the ARID1A and PIK3CA are high-frequency mutations of OCCC. Clonal architectures showed that all the mutations of genes occur in the later stage in the OCCC progress, whereas KRAS mutation is the earlier event compared with mutation of ARID1A or PIK3CA, which usually occurs in a group of ARID1A or PIK3CA mutations. The mutation frequency of main driver genes is similar between OCCC and ECCC, while TP53 is the main mutation in HGSOC and ECCC. Shared mutational signatures between OCCC and ECCC tissues with commonly observed a C>T change indicated a common carcinogens-exposed between these two carcinomas, but HGSOC and ECCC have common and distinct mutational signatures across cohorts respectively. In addition, we identified some novel CNV gains in NF1, ASXL1, TCF7L2, CREBBP and LRP1B and loss in ATM, FANCM, RB1 and FLT in OCCC. Our study offered a new perspective for OCCC tumorigenesis from two organs, the ovary and uterus, at genomic architectures and revealed novel CNV events for helping to provide theoretical support for OCCC treatment.

Lymphoid-specific helicase inhibits cervical cancer cells ferroptosis by promoting Nrf2 expression

Background Cervical cancer is a major cause of morbidity and mortality in women worldwide. The underlying mechanisms of its progression are not well understood. In this study, we investigated the role of lymphoid-specific helicase (HELLS) in cervical cancer. Methods We measured HELLS expression in cervical cancer and assessed its function using gain- and loss-of-function experiments. Cell viability was measured using the Cell Counting Kit-8 (CCK8 ) assay, and cell proliferation was analyzed using colony formation and EdU assays. Results We found that HELLS was significantly increased in cervical cancer and that its overexpression promoted cell viability (P < 0.01) and colony formation (P < 0.001). In contrast, si-HELLS suppressed these effects. Moreover, HELLS overexpression inhibited cell death induced by the ferroptosis inducer erastin (P < 0.01). Mechanistically, we found that HELLS promoted cervical cancer proliferation by regulating nuclear factor erythroid 2-related factor 2 (Nrf2)-mediated ferroptosis. Conclusion Our data suggest that HELLS promotes cervical cancer proliferation by inhibiting Nrf2 expression. Therefore, HELLS knockdown may be an effective treatment for cervical cancer.

Chromatin accessibility complex subunit 1 enhances tumor growth by regulating the oncogenic transcription of YAP in breast and cervical cancer

Background As a component of chromatin remodeling complex, chromatin accessibility complex subunit 1 (CHRAC1) is critical in transcription and DNA replication. However, the significance of CHRAC1 in cancer progression has not been investigated extensively. This research aimed to determine the function of CHRAC1 in breast and cervical cancer and elucidate the molecular mechanism. Methods The Bio-ID method was used to identify the interactome of transcriptional activator Yes-associated protein (YAP) and the binding between YAP and CHRAC1 was verified by immunofluorescence. CCK8, colony formation and subcutaneous xenograft assays were conducted to explore the function of CHRAC1 in cancer cell proliferation. RNA-seq analysis and RT-PCR were used to analyze the transcription program change after CHRAC1 ablation. The diagnostic value of CHRAC1 was analyzed by TCGA database and further validated by immunohistochemistry staining. Results In the current study, we found that the chromatin remodeler CHRAC1 was a potential YAP interactor. CHRAC1 depletion suppressed breast and cervical cancer cell proliferation and tumor growth. The potential mechanism may be that CHRAC1 interacts with YAP to facilitate oncogenic transcription of YAP target genes in Hippo pathway, thereby promoting tumorigenesis. CHRAC1 was elevated in cervical and breast cancer biopsies and the upregulation correlated with shorter survival, poor pathological stages and metastasis of cancer patients. Moreover, CHRAC1 expression was statistically associated with YAP in breast and cervical cancer biopsies. Conclusions These findings highlight that CHRAC1 contributes to cancer progression through regulating the oncogenic transcription of YAP, which makes it a potential therapeutic target for cancer treatment.

CESCProg: a compact prognostic model and nomogram for cervical cancer based on miRNA biomarkers

Cervical squamous cell carcinoma, more commonly cervical cancer, is the fourth common cancer among women worldwide with substantial burden of disease, and less-invasive, reliable and effective methods for its prognosis are necessary today. Micro-RNAs are increasingly recognized as viable alternative biomarkers for direct diagnosis and prognosis of disease conditions, including various cancers. In this work, we addressed the problem of systematically developing an miRNA-based nomogram for the reliable prognosis of cervical cancer. Towards this, we preprocessed public-domain miRNA -omics data from cervical cancer patients, and applied a cascade of filters in the following sequence: (i) differential expression criteria with respect to controls; (ii) significance with univariate survival analysis; (iii) passage through dimensionality reduction algorithms; and (iv) stepwise backward selection with multivariate Cox modeling. This workflow yielded a compact prognostic DEmiR signature of three miRNAs, namely hsa-miR-625-5p, hs-miR-95-3p, and hsa-miR-330-3p, which were used to construct a risk-score model for the classification of cervical cancer patients into high-risk and low-risk groups. The risk-score model was subjected to evaluation on an unseen test dataset, yielding a one-year AUROC of 0.84 and five-year AUROC of 0.71. The model was validated on an out-of-domain, external dataset yielding significantly worse prognosis for high-risk patients. The risk-score was combined with significant features of the clinical profile to establish a predictive prognostic nomogram. Both the miRNA-based risk score model and the integrated nomogram are freely available for academic and not-for-profit use at CESCProg, a web-app ( https://apalania.shinyapps.io/cescprog ).

Fine-scale mapping of chromosome 9q22.33 identifies candidate causal variant in ovarian cancer

Ovarian cancer is a complex polygenic disease in which genetic factors play a significant role in disease etiology. A genome-wide association study (GWAS) identified a novel variant on chromosome 9q22.33 as a susceptibility locus for epithelial ovarian cancer (EOC) in the Han Chinese population. However, the underlying mechanism of this genomic region remained unknown. In this study, we conducted a fine-mapping analysis of 130 kb regions, including 1,039 variants in 200 healthy women. Ten variants were selected to evaluate the association with EOC risk in 1,099 EOC cases and 1,591 controls. We identified two variants that were significantly associated with ovarian cancer risk (rs7027650, P = 1.91 × 10−7; rs1889268, P = 3.71 × 10−2). Expression quantitative trait locus (eQTL) analysis found that rs7027650 was significantly correlated with COL15A1 gene expression (P = 0.009). The Luciferase reporter gene assay confirmed that rs7027650 could interact with the promoter region of COL15A1, reducing its activity. An electrophoretic mobility shift assay (EMSA) showed the allele-specific binding capacity of rs7027650. These findings revealed that rs7027650 could be a potential causal variant at 9q22.33 region and may regulate the expression level of COL15A1. This study offered insight into the molecular mechanism behind a potential causal variant that affects the risk of ovarian cancer.

Prediction study of prognostic nutrition index on the quality of life of patients with cervical cancer undergoing radiotherapy and chemotherapy

Objective To assess the prognostic nutritional index (PNI) and quality of life (QOL) of patients with cervical cancer (CC) who underwent radiotherapy and chemotherapy and to reveal the effect of PNI on QOL and its prognostic value. Methods A total of 138 CC patients who underwent radiotherapy and chemotherapy in the Second Affiliated Hospital of Fujian Medical University from January 2020 to October 2022 were selected as the study subjects via convenient sampling. According to the PNI cut-off value of 48.8, they were divided into a high-PNI group and a low-PNI group, and the quality of life of the two groups was compared. The Kaplan-Meier method was used to draw the survival curve, and the Log-Rank test was employed to compare the survival rates of the two groups. Results The scores of physical functioning and overall QOL in the high-PNI group were significantly higher than those in the low-PNI group (P < 0.05). The scores of fatigue, nausea and vomiting, pain and diarrhea were higher than those in the low-PNI group, and the difference was statistically significant (P < 0.05). The objective response rates were 96.77% and 81.25% in the high-PNI group and the low-PNI group, respectively, and the difference was statistically significant (P = 0.045). The 1-year survival rates of patients with high PNI and low PNI were 92.55% and 72.56% in the high-PNI group and the low-PNI group, respectively; the difference in survival rates was statistically significant (P = 0.006). Conclusion The overall quality of life of CC patients with low PNI receiving radiotherapy and chemotherapy is lower than that of patients with high PNI. Low PNI reduces the tolerance to radiotherapy and chemotherapy and the objective response rate, which can be used as a prognostic indicator for cervical cancer patients.

Development of a relapse-related RiskScore model to predict the drug sensitivity and prognosis for patients with ovarian cancer

Background Ovarian cancer (OC) is a highly aggressive malignancy in the reproductive system of women, with a high recurrence rate. The present research was designed to establish a relapse-based RiskScore model to assess the drug sensitivity and prognosis for patients with OC. Methods Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) databases were accessed to obtain relevant sample data. The single-cell atlas of primary and relapse OC was characterized using the “Seurat” package. Differentially expressed genes (DEGs) between primary and relapse samples were identified by FindMarkers function. Subsequently, univariate Cox, least absolute shrinkage and selection operator (LASSO) and stepwise regression analysis were employed to determine independent prognostic genes related to relapse in OC to establish a RiskScore model. Applying “timeROC” package, the predictive performance of RiskScore model was assessed. Drug sensitivity of different risk groups was evaluated using “pRRophetic” package. The effects of relapse-related prognostic genes on OC cells were detected with in vitro assays. Results The single-cell atlas revealed that compared to primary OC, fibroblasts were reduced but epithelial cells were increased in relapse OC. Five prognostic genes (LDHA, NOP58, NMU, KRT19, and RPS23) independently linked to relapse in OC were identified to construct a RiskScore model, which showed high robustness in the prognostic prediction for OC patients. High-risk group tended to have worse outcomes in terms of different clinical features than the low-risk group. Further, six drugs (Vinorelbine, GW-2580, S-Trityl-L-cysteine, BI-2536, CP466722, NSC-87877) were found to be correlated with the RiskScore. While the high-risk group had higher IC50 values to these drugs, the low-risk group was more sensitive to the six drugs. In addition, KRT19 silencing markedly inhibited the invasion and migration of OC cells. Conclusion This study established a relapse-related RiskScore model based on five prognostic genes (LDHA, NOP58, NMU, KRT19, and RPS23), offering novel insights into the recurrence mechanisms in OC and contributing to the development of individualized treatment strategies.

MicroRNA-597-3p targets MACC1 to suppress proliferation and invasion of human ovarian cancer cells

Background Ovarian cancer is a lethal gynecological malignancy, largely due to late-stage diagnosis and poor prognosis. MicroRNA-597-3p (miR-597-3p) has been identified as a tumor suppressor in several cancers, while metastasis-associated colon cancer 1 (MACC1) functions as an oncogene that promotes metastasis. This study investigated the role of miR-597-3p and its regulation of MACC1 in ovarian cancer progression. Methods Ovarian cancer cell lines and the normal ovarian epithelial cell line IOSE-398 were used. Quantitative real-time PCR (qRT-PCR) measured the expression of miR-597-3p and MACC1. Functional assays (MTT, colony formation, AO/EB staining, and Transwell invasion) evaluated cell proliferation, cell death, and invasion. Dual-luciferase reporter assays confirmed the interaction between miR-597-3p and MACC1, while bioinformatics analysis identified potential targets. Western blotting was used to validate MACC1 and downstream proteins, MMP-2, and MMP-9 at the protein level. Results MiR-597-3p was significantly downregulated ( P  < 0.05) in ovarian cancer cells, whereas MACC1 was upregulated. Overexpression of miR-597-3p suppressed cell viability, colony formation, and invasion, and increased cell death with a pro-apoptotic shift in Bax/Bcl-2 expression. Mechanistically, miR-597-3p directly targeted MACC1, leading to reduced expression of MMP-2 and MMP-9 at both transcript and protein levels. Notably, MACC1 overexpression reversed the tumor-suppressive effects of miR-597-3p. Conclusions MiR-597-3p functions as a tumor suppressor in ovarian cancer by directly targeting MACC1, thereby inhibiting proliferation, invasion, and survival. These findings highlight the miR-597-3p/MACC1 axis as a potential therapeutic target and suggest miR-597-3p as a promising biomarker for ovarian cancer.

Seroprevalence of Toxoplasma gondii infection in women with a gynecological tumor living in eastern China

The association between Toxoplasma gondii (T. gondii) infection and malignancy has attracted increased attention in recent years, but little is known of T. gondii infection among women diagnosed with a gynecological tumor (GT) in China. We conducted a case-control study involving 460 women diagnosed with a GT and 460 age-matched healthy controls (HCs) to estimate the infection process of T. gondii and understand the risk factors of T. gondii infection in patients with a GT. Levels of anti-T. gondii IgG and IgM were measured by enzyme-linked immunoassays every 12 months. After a median follow-up time of 4.3 years (range 4 to 5 years), 55/460 (11.96%) patients with a GT and 15/460 (3.26%) HCs were seroprevalence for T. gondii antibodies, respectively (P = 0.001). IgG antibodies against T. gondii were found in 54 GT patients (11.74%) and 15 HCs (3.26%), respectively (P = 0.001). The seroprevalence of T. gondii IgM antibodies was similar in patients with a GT and with HCs (2.83% vs 1.3%, P = 0.105). Multivariate stepwise logistic regression analysis revealed contact with cats (OR, 6.67; 95% CI [2.89–10.75]; P = 0.001), exposure to soil (OR, 2.16; 95% CI [1.14–4.10]; P = 0.019), being a farm-worker (OR, 4.17; 95% CI [1.20–11.49]; P = 0.006) and history of chemotherapy (OR, 3.16; 95% CI [1.56–6.45]; P = 0.001) to be independent risk factors for T. gondii infection. Women with an ovarian cancer or endometrial cancer had higher T. gondii seroprevalence than that of HCs. Moreover, T. gondii infection in patients with a GT mostly acquired within two years of diagnosis, but the infection in healthy controls had no obvious time characteristics. Here, we demonstrated that T. gondii infection is significantly higher in patients with a GT (especially in women with an ovarian tumor) compared to HCs. Thus, infection with this parasite should be avoided in patients with a GT, and the causal relationship between T. gondii and GTs should be studied in detail.

Tumor budding of cervical squamous cell carcinoma: epithelial-mesenchymal transition-like cancer stem cells?

Recent evidence indicates that cancer stem cells (CSCs) are the origin of cancers. Scientists have identified CSCs in various tumors and have suggested the existence of a variety of states of CSCs. The existence of epithelial–mesenchymal transition (EMT)-like CSCs has been confirmed in vitro , but they have not been identified in vivo . Tumor budding was defined as single cell or clusters of ≤ 5 cells at the invasive front of cancers. Such tumor budding is hypothesized to be closely related to EMT and linked to CSCs, especially to those migrating at the invasive front. Therefore, tumor budding has been proposed to represent EMT-like stem cells. However, this hypothesis has not yet been proven. Thus, we studied the expression of EMT markers, certain CSC markers of tumor budding, and the tumor center of cervical squamous cell carcinoma (CxSCC). We performed tissue chip analyses of 95 primary CxSCCs from patients. Expression of EMT and CSC markers (E-cadherin, β -catenin, vimentin, Ki67, CD44, SOX2 , and ALDH1A1) in a set of tumor samples on tissue chips (87 cases of tumor budding/the main tumor body) were evaluated by immunohistochemistry. We found that the cell-membranous expression of β -catenin was stronger in the main tumor body than in tumor buds. Compared with the main tumor body, tumor buds had reduced proliferative activity as measured by Ki67. Moreover, vimentin expression was high and E-cadherin expression was low in tumor buds. Expression of EMT-related markers suggested that tumor buds were correlated with EMT. We noted that CxSCC tumor buds had a CD44 negative/low /SOX2 high /ALDH1A1 high staining pattern, indicating that tumor buds of CxSCC present CSC-like immunophenotypic features. Taken together, our data indicate that tumor buds in CxSCC may represent EMT-like CSCs in vivo.

Transcriptome analysis reveals the potential biological function of FSCN1 in HeLa cervical cancer cells

Fascin actin-bundling protein 1 (FSCN1), an actin-bundling protein associated with cell migration and invasion, is highly expressed in various tumor tissues. FSCN1 has also been reported to be a marker of increased invasive potential in cervical cancers. However, the functions of FSCN1 are still not fully understood in cervical cancers. Here, the gene expression profile of HeLa cells transfected with FSCN1 shRNA (shFSCN1) was compared with that of cells transfected with empty vector (shCtrl). The results showed that shFSCN1 extensively affected the transcription level of 5,043 genes in HeLa cells. In particular, Gene Ontology (GO) analysis showed that a large number of upregulated genes were annotated with terms including transcription regulation and DNA binding. The downregulated genes were enriched in some cancer pathways, including angiogenesis and cell adhesion. qPCR validation confirmed that FSCN1 knockdown significantly affected the expression of selected genes in HeLa cells either negatively or positively. Expression analysis in TCGA (The Cancer Genome Atlas) revealed that FSCN1 had negative correlations with several transcription factors and a positive correlation with an angiogenic factor (angiopoietin like 4, ANGPTL4) in cervical tumor tissue. In particular, validation by Western blotting showed that FSCN1 knockdown decreased the protein level of ANGPTL4. Our results demonstrated that FSCN1 is not only an actin-binding protein but also a transcriptional regulator and an angiogenic factor in cervical cancer. Thus, our study provides important insights for further study on the regulatory mechanism of FSCN1 in cervical cancer.

YAP1 affects the prognosis through the regulation of stemness in endometrial cancer

Background Endometrial cancer stem-like cells (ECSCs) have been proven to be responsible for recurrence, metastasis, and drug-resistance in patients with endometrial cancer. The HIPPO pathway has been shown to play an important role in the development and maintenance of stemness in a variety of tumors. While there was less research about its function in ECSCs. The aim of this study was to explore the role of YAP1, a core molecular of HIPPO pathway, in the stemness of endometrial cancer and to reveal its influence on prognosis. Methods We collected specimens and clinical data from 774 patients with endometrial cancer to analyze the correlation between YAP1 expression and prognosis. We then examined the expression of YAP1 in ECSCs and EC cell lines (Ishikawa; HEC1-A) in vitro experiments. Changes in the stemness of cell lines were detected after YAP1 silencing by siRNA. Finally, high-throughput sequencing was used to predict the potential molecular interactions and mechanisms of YAP1’s effect on stemness. Result Down-regulation of YAP1 significantly suppresses the stemness of EC cell lines. High expression of YAP1 leads to poor prognosis in EC by regulation of stemness. Conclusion YAP1 plays an important role in the prognosis of patients with EC by regulation of stemness.

Simpler predictive models provide higher accuracy for ovarian cancer detection

Ovarian cancer remains a danger to women’s health, and accurate screening tests would likely increase survival. Two established protein biomarkers, CA125 and HE4, have been shown to work well in isolation, but achieve even higher accuracy when combined using logistic regression (LR). This LR-based combination of protein concentrations achieves high accuracy when distinguishing healthy samples from cancer samples (area under the curve (AUC) = 0.99). The dataset we use was obtained from a previous publication that described DELFI-Pro, an LR model combining features derived from cell-free DNA (cfDNA) with the two proteins’ concentrations. We show that many of DELFI-Pro’s cfDNA features are affected by confounding technical variation within training data, which impacts the previously reported results. A minority of the training data’s cancer samples (42 of 94) have chromosomal copy number values that are markedly different from the other samples used to evaluate the DELFI-Pro screening model. After removing those 42 samples from the training data, we find that DELFI-Pro does not outperform CA125 or CA125+HE4 protein-only screening classifiers even in cross validation, including a two-protein model published alongside the DELFI-Pro model. We conclude that DELFI-Pro does not adequately justify the inclusion of its cfDNA features. Our results are in line with the principle that simpler machine learning models will tend to exhibit better generalizability on new data.

Identification of immunogenic cell death gene-related subtypes and risk model predicts prognosis and response to immunotherapy in ovarian cancer

Background Immunogenic cell death (ICD) has been associated with enhanced anti-tumor immunotherapy by stimulating adaptive immune responses and remodeling the immune microenvironment in tumors. Nevertheless, the role of ICD-related genes in ovarian cancer (OC) and tumor microenvironment remains unexplored. Methods In this study, high-throughput transcriptomic data from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases as training and validation sets separately were obtained and proceeded to explore ICD-related clusters, and an ICD-related risk signature was conducted based on the least absolute shrinkage and selection operator (LASSO) Cox regression model by iteration. Multiple tools including CIBERSORT, ESTIMATE, GSEA, TIDE, and immunohistochemistry were further applied to illustrate the biological roles of ICD-related genes as well as the prognostic capacity of ICD risk signature in OC. Results Two ICD-related subtypes were identified, with the ICD-high subtype showing more intense immune cell infiltration and higher activities of immune response signaling, along with a favorable prognosis. Additionally, four candidate ICD genes (IFNG, NLRP3, FOXP3, and IL1B) were determined to potentially impact OC prognosis, with an upregulated expression of NLRP3 in OC and metastatic omental tissues. A prognostic model based on these genes was established, which could predict overall survival (OS) and response to immunotherapy for OC patients, with lower-risk patients benefiting more from immunotherapy. Conclusion Our research conducted a prognostic and prediction of immunotherapy response model based on ICD genes, which could be instrumental in assessing prognosis and assigning immunotherapeutic strategies for OC patients. NLRP3 is a promising target for prognosis in OC.

Knowledge and application of sonographic scoring models for ovarian cancer management among gynecologists in Saudi Arabia: a cross-sectional study

Background Ovarian cancer is a significant global health concern, ranking as the seventh most common cancer and the eighth leading cause of cancer-related deaths among women. Annually, it claims the lives of approximately 207,000 women worldwide. Early detection is crucial, as most cases are diagnosed at advanced stages, resulting in a 5-year survival rate of less than 20%. Common diagnostic tools include Cancer Antigen 125 (CA125) and ultrasound, but these methods are limited by sensitivity, specificity, and operator dependence. The Risk of Malignancy Index (RMI) and the Assessment of Different NEoplasias in the Adnexa (ADNEX) model, which integrates ultrasound and CA125, offer improved diagnostic accuracy. This study aims to assess the knowledge and application of these models among gynecologists in Saudi Arabia. Methods A cross-sectional study was conducted involving 148 gynecologists from various hospitals in Saudi Arabia. Participants completed a structured questionnaire that was distributed online, designed to evaluate their knowledge and application of the RMI and ADNEX models. Data were analyzed using descriptive statistics, and factors influencing the utilization of these models were identified through multivariate logistic regression analysis. Results The study found that 72% of the gynecologists were familiar with the RMI, and 58% were aware of the ADNEX model. However, only 46% reported regularly using the RMI, and 32% used the ADNEX model in their practice. Key barriers to the application of these models included a lack of training (56%), and limited access to necessary diagnostic tools (48%). Gynecologists with more than 10 years of experience were significantly more likely to use the RMI (odds ratio (OR): 2.5, 95% confidence interval (CI) [1.3–4.8]) and the ADNEX model (OR: 2.1, 95% CI [1.1–4.0]). Conclusion In Saudi Arabia, gynecologists show moderate knowledge of sonographic scoring models for ovarian cancer management, with higher familiarity for RMI than ADNEX. However, application in clinical practice is limited. Experience level influences usage, while lack of training and diagnostic access remain key barriers. Targeted educational efforts and improved resource availability are needed to support broader clinical adoption.