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Aging

Papers (133)

A stemness-based signature with inspiring indications in discriminating the prognosis, immune response, and somatic mutation of endometrial cancer patients revealed by machine learning

Endometrial cancer (EC) is a fatal gynecologic tumor. Bioinformatic tools are increasingly developed to screen out molecular targets related to EC. Our study aimed to identify stemness-related prognostic biomarkers for new therapeutic strategies in EC. In this study, we explored the prognostic value of cancer stem cells (CSCs), characterized by self-renewal and unlimited proliferation, and its correlation with immune infiltrates in EC. Transcriptome and somatic mutation profiles of EC were downloaded from TCGA database. Based on their stemness signature and DEGs, EC patients were divided into two subtypes via consensus clustering, and patients in Stemness Subtype I presented significantly better OS and DFS than Stemness Subtype II. Subtype I also displayed better clinicopathological features, and genomic variations demonstrated different somatic mutation from subtype II. Additionally, two stemness subtypes had distinct tumor immune microenvironment patterns. In the end, three machine learning algorithms were applied to construct a 7-gene stemness subtype risk model, which were further validated in an external independent EC cohort in our hospital. This novel stemness-based classification could provide a promising prognostic predictor for EC and may guide physicians in selecting potential responders for preferential use of immunotherapy. This novel stemness-dependent classification method has high value in predicting the prognosis, and also provides a reference for clinicians in selecting sensitive immunotherapy methods for EC patients.

Identification and validation of anoikis-related lncRNAs for prognostic significance and immune microenvironment characterization in ovarian cancer

Anoikis, a form of apoptotic cell death resulting from inadequate cell-matrix interactions, has been implicated in tumor progression by regulating tumor angiogenesis and metastasis. However, the potential roles of anoikis-related long non-coding RNAs (arlncRNAs) in the tumor microenvironment are not well understood. In this study, five candidate lncRNAs were screened through least absolute shrinkage and selection operator (LASSO), and multivariate Cox regression analysis based on differentially expressed lncRNAs associated with anoikis-related genes (ARGs) from TCGA and GSE40595 datasets. The prognostic accuracy of the risk model was evaluated using Kaplan-Meier survival analysis and receiver operating characteristic (ROC) curves. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) and gene set enrichment analysis (GSEA) analyses revealed significant differences in immune-related hallmarks and signal transduction pathways between the high-risk and low-risk groups. Additionally, immune infiltrate analysis showed significant differences in the distribution of macrophages M2, follicular T helper cells, plasma cells, and neutrophils between the two risk groups. Lastly, silencing the expression of PRR34_AS1 and SPAG5_AS1 significantly increased anoikis-induced cell death in ovarian cancer cells. In conclusion, our study constructed a risk model that can predict clinicopathological features, tumor microenvironment characteristics, and prognosis of ovarian cancer patients. The immune-related pathways identified in this study may offer new treatment strategies for ovarian cancer.

ACE2 correlated with immune infiltration serves as a prognostic biomarker in endometrial carcinoma and renal papillary cell carcinoma: implication for COVID-19

Angiotensin-converting enzyme 2 (ACE2) is a member of the renin-angiotension system, however, the correlation between ACE2 and prognosis in UCEC (Uterine Corpus Endometrial Carcinoma) and KIRP (Kidney Renal Papillary Cell Carcinoma) is not clear. We analyzed the expression levels of ACE2 in the Oncomine and TIMER databases, the correlation between ACE2 and overall survival in the PrognoScan, GEPIA and Kaplan-Meier plotter databases. The correlation between ACE2 and immune infiltration level and the type markers of immune cells was investigated in TIMER database. A prognosis analysis based on the expression levels of ACE2 was further performed in related immune cells subgroup. The ACE2 promoter methylation profile was tested in the UALCAN database. In addition, we used GSE30589 and GSE52920 databases to elucidate the changes of ACE2 expression in vivo and in vitro after SARS-CoV infection. ACE2 was elevated in UCEC and KIRP, and high ACE2 had a favorable prognosis. The expression of ACE2 was positively correlated with the level of immune infiltration of macrophage in KIRP, B cell, CD4+T cell, neutrophil and dendritic cell immune infiltration levels in UCEC. ACE2 was significantly positively correlated with the type markers of B cells and neutrophils, macrophages in UCEC, while ACE2 in KIRP was positively correlated with the type markers of macrophages. High ACE2 expression level had a favorable prognosis in different enriched immune cells subgroups in UCEC and KIRP. And the promoter methylation levels of ACE2 in UCEC and KIRP were significantly reduced. What's more, we found that the expression of ACE2 decreased in vivo and in vitro after SARS-CoV infection. In conclusion, ACE2 expression increased significantly in UCEC and KIRP, elevated ACE2 was positively correlated with immune infiltration and prognosis. Moreover, tumor tissues may be more susceptible to SARS-CoV-2 infection in COVID-19 patients with UCEC and KIRP, which may worsen the prognosis.

Construction of a new tumor immunity-related signature to assess and classify the prognostic risk of ovarian cancer

Ovarian cancer is associated with a high mortality rate. In this study, we established a new immune-related signature that can stratify ovarian cancer patients. First, we obtained immune-related genes through IMMUPORT, and DEGs (Differential Expression Genes) by analyzing the GSE26712 dataset. The APP (Antigen Processing and Presentation) and DEG signatures were established using univariate and multivariate Cox models. Kaplan-Meier analysis revealed the signatures' prognostic value in training and validation cohorts (HR: 0.379 VS. 0.450; 0.333 VS. 0.327). Nomogram analysis was used to assess the signatures' ability to predict the 30-month prognosis, which was evaluated using the calibration curve and time-dependent ROC curve (30-month AUC: 0.665 VS. 0.743). Time-dependent ROC, Decision Curve Analysis (DCA) and Integrated discrimination improvement (IDI) was used to compare the new model to previously published gene signatures. 30-month AUC composite variable (0.736) was higher than 9-gene signature (0.657), and composite variable had a larger net benefit and a higher IDI (+2.436%) relative to the 9-gene signature. Tumor immune infiltration and tumor microenvironment scores of the 2 groups separated by APP signature were compared. GSEA was used to identify enriched KEGG pathways. Conclusively, the proposed signature can stratify ovarian cancer patients by risk-score and guide clinical decisions.

An individualized transcriptional signature to predict the epithelial-mesenchymal transition based on relative expression ordering

The epithelial-mesenchymal transition (EMT) process is involved in cancer cell metastasis and immune system activation. Hence, identification of gene expression signatures capable of predicting the EMT status of cancer cells is essential for development of therapeutic strategies. However, quantitative identification of EMT markers is limited by batch effects, the platform used, or normalization methods. We hypothesized that a set of EMT-related relative expression orderings are highly stable in epithelial samples yet are reversed in mesenchymal samples. To test this hypothesis, we analyzed transcriptome data for ovarian cancer cohorts from publicly available databases, to develop a qualitative 16-gene pair signature (16-GPS) that effectively distinguishes the mesenchymal from epithelial phenotype. Our method was superior to previous quantitative methods in terms of classification accuracy and applicability to individualized patients without requiring data normalization. Patients with mesenchymal-like ovarian cancer showed poorer overall survival compared to patients with epithelial-like ovarian cancer. Additionally, EMT score was positively correlated with expression of immune checkpoint genes and metastasis. We, therefore, established a robust EMT 16-GPS that is independent of detection platform, batch effects and individual variations, and which represents a qualitative signature for investigating the EMT and providing insights into immunotherapy for ovarian cancer patients.

Long non-coding RNA RHPN1-AS1 promotes tumorigenesis and metastasis of ovarian cancer by acting as a ceRNA against miR-596 and upregulating LETM1

In recent decades, long non-coding RNAs (lncRNAs) have been reported as crucial functional regulators involved in ovarian cancer. In the present study, we explored how lncRNA RHPN1-AS1 influences the progression of epithelial ovarian cancer (EOC) through tumor cell-dependent mechanisms. The expression of RHPN1-AS1 in EOC tissues was higher than that in para-cancerous control tissues. High expression of RHPN1-AS1 was closely associated with poor prognosis in EOC patients. N6-methyladenosine (m6A) improved the stability of RHPN1-AS1 methylation transcript by reducing RNA degradation, which resulted in upregulation of RHPN1-AS1 in EOC. In vitro and in vivo functional experiments showed that RHPN1-AS1 promoted EOC cell proliferation and metastasis. RHPN1-AS1 acted as a ceRNA to sponge miR-596, consequently increasing LETM1 expression and activating the FAK/PI3K/Akt signaling pathway. RHPN1-AS1-miR-596-LETM1 axis plays a crucial role in EOC progression. Our findings may provide promising drug targets for EOC treatment. We determined the aberrantly expressed lncRNAs in EOC via microarray analysis and validated RHPN1-AS1 expression by qRT-PCR. The RHPN1-AS1-miR-596-LETM1 axis was examined by dual-luciferase reporter assay and RIP assay. The mechanism of RHPN1-AS1 was investigated through gain- and loss-of-function studies both in vivo and in vitro.

NAC1 attenuates BCL6 negative autoregulation and functions as a BCL6 coactivator of FOXQ1 transcription in cancer cells

Nucleus accumbens-associated protein 1 (NAC1) has multifaceted roles in cancer pathogenesis and progression, including the development of drug resistance, promotion of cytokinesis, and maintenance of "stem cell-like" phenotypes. NAC1 is a transcriptional co-regulator belonging to the bric-a-brac tramtrack broad (BTB) family of proteins, although it lacks the characteristic DNA binding motif of the BTB family. The formation of higher-order transcription complexes likely depends on its interaction with other DNA-binding co-factors. NAC1 interacts with BCL6 via its C-terminal BEN domain and forms a complex that binds the promoter region and activates transcription of the NAC1 target gene, FOXQ1. NAC1 and BCL6 were coordinately upregulated. Our analysis also identified a novel function of NAC1 in attenuating BCL6 auto-downregulation in ovarian cancer. Lastly, we found a significant overlap among NAC1- and BCL6-regulated genes in tumor cells, suggesting that NAC1 and BCL6 coordinately control transcription in cancer. The results of this study provide a novel mechanistic insight into the oncogenic roles of NAC1 and underline the importance of developing the NAC1/BCL6-targeted cancer therapy. Using the Cistrome database and Chromatin Immunoprecipitation (ChIP) analyses, we identified BCL6 as a potential NAC1- interacting molecule. Co-immunoprecipitation (Co-IP), luciferase reporter assay, immunohistochemistry and microarray analysis were performed to analyze the interaction between NAC1 and BCL6 and the mechanisms by which they regulate the downstream genes including FOXQ1.

Genome-wide DNA copy number profiling and bioinformatics analysis of ovarian cancer reveals key genes and pathways associated with distinct invasive/migratory capabilities

Ovarian cancer (OC) metastasis presents major hurdles that must be overcome to improve patient outcomes. Recent studies have demonstrated copy number variations (CNVs) frequently contribute to alterations in oncogenic drivers. The present study used a CytoScan HD Array to analyse CNVs and loss of heterozygosity (LOH) in the entire genomes of 6 OC patients and human OC cell lines to determine the genetic target events leading to the distinct invasive/migratory capacities of OC. The results showed that LOH at Xq11.1 and Xp21.1 and gains at 8q21.13 were novel, specific CNVs. Ovarian cancer-related CNVs were then screened by bioinformatics analysis. In addition, transcription factors-target gene interactions were predicted with information from PASTAA analysis. As a result, six genes (i.e., GAB2, AKT1, EGFR, COL6A3, UGT1A1 and UGT1A8) were identified as strong candidates by integrating the above data with gene expression and clinical outcome data. In the transcriptional regulatory network, 4 known cancer-related transcription factors (TFs) interacted with 6 CNV-driven genes. The protein/DNA arrays revealed 3 of these 4 TFs as potential candidate gene-related transcription factors in OC. We then demonstrated that these six genes can serve as potential biomarkers for OC. Further studies are required to elucidate the pathogenesis of OC.

Identification of the miRNA signature associated with survival in patients with ovarian cancer

Ovarian cancer is a major gynaecological malignant tumor associated with a high mortality rate. Identifying survival-related variants may improve treatment and survival in patients with ovarian cancer. In this work, we proposed a support vector regression (SVR)-based method called OV-SURV, which is incorporated with an inheritable bi-objective combinatorial genetic algorithm for feature selection to identify a miRNA signature associated with survival in patients with ovarian cancer. There were 209 patients with miRNA expression profiles and survival information of ovarian cancer retrieved from The Cancer Genome Atlas database. OV-SURV achieved a mean correlation coefficient of 0.77±0.01and a mean absolute error of 0.69±0.02 years using 10-fold cross-validation. Analysis of the top ranked miRNAs revealed that the miRNAs, hsa-let-7f, hsa-miR-1237, hsa-miR-98, hsa-miR-933, and hsa-miR-889, were significantly associated with the survival in patients with ovarian cancer. Kyoto Encyclopedia of Genes and Genomes pathway analysis revealed that four of these miRNAs, hsa-miR-182, hsa-miR-34a, hsa-miR-342, and hsa-miR-1304, were highly enriched in fatty acid biosynthesis, and the five miRNAs, hsa-let-7f, hsa-miR-34a, hsa-miR-342, hsa-miR-1304, and hsa-miR-24, were highly enriched in fatty acid metabolism. The prediction model with the identified miRNA signature consisting of prognostic biomarkers can benefit therapeutic decision making of ovarian cancer.

A bioinformatic analysis: the overexpression and clinical significance of FCGBP in ovarian cancer

Fc fragment of IgG-binding protein (FCGBP) is differentially expressed in various tumors. However, the correlation between FCGBP and immune cell infiltration in ovarian cancer remains unclear. FCGBP expression was analyzed using The Cancer Genome Atlas (TCGA) pan-cancer data, and the ovarian cancer expression profile was analyzed using the Gene Expression Omnibus database. The clinical prognostic value of FCGBP was evaluated using clinical survival data from TCGA. Enrichment analysis of FCGBP was performed using the R package clusterProfiler. Based on known immune cell infiltration scores for samples found in TCGA, we analyzed the association between immune cell infiltration level and FCGBP expression. FCGBP was highly expressed and associated with poorer overall survival (p = 0.00051) and disease-specific survival (p = 0.0012) in ovarian cancer and other tumors. Additionally, high FCGBP expression correlated significantly with immune-related gene sets, including those involved in chemokine signaling pathways and innate and adaptive immunity. Further analysis showed that M2 macrophage infiltration increased and M1 macrophage infiltration decreased in tissues with high FCGBP expression. Our study suggests that FCGBP contributes to M2 macrophage polarization by acting as an oncogene in ovarian cancer. FCGBP may represent a clinically helpful biomarker for predicting overall survival of ovarian cancer patients.

miRNA-142-3p functions as a potential tumor suppressor directly targeting FAM83D in the development of ovarian cancer

FAM83D (family with sequence similarity 83, member D) is of particular interest in tumorigenesis and tumor progression. Ovarian cancer is the leading cause of cancer-related death in women all over the world. This study aims to research the association between FAM83D and ovarian cancer (OC). The gene expression data of OC and normal samples (GSE81873 and GSE27651) was downloaded from Gene Expression Omnibus (GEO) dataset. The bioinformatics analysis was performed to distinguish two differentially expressed genes (DEGs), prognostic candidate genes and functional enrichment pathways. Immunohistochemistry (IHC), Quantitative Real-time PCR (qPCR), and luciferase reporter assays were utilized for further study. There were 56 DEMs and 63 DEGs in cancer tissues compared to normal tissues. According to the km-plot software, hsa-miR-142-3p and FAM83D were associated with the overall survival of patients with OC. Besides, Multivariate analysis included that hsa-miR-142-3p and FAM83D were independent risk factors for OC patients. Furthermore, qPCR demonstrated that miRNA-142-3p and FAM83D were differentially expressed in normal ovarian tissues (NOTs) and ovarian cancer tissues (OCTs). IHC results indicated that FAM83D was overexpressed in OCTs compared with NOTs. Last but not least, luciferase reporter assays verified that FAM83D was a direct target of hsa-miRNA-142-3p in OC cells. The prognostic model based on the miRNA-mRNA network could provide predictive significance for the prognosis of OC patients, which would be worthy of clinical application. Our results concluded that miR-142-3p and its targets gene FAM83D may be potential diagnostic and prognostic biomarkers for patients with OC.

Tumor purity as a prognosis and immunotherapy relevant feature in cervical cancer

Tumor purity plays a vital role in the biological process of solid tumors, but its function in gynecologic cancers remains unclear. This study explored the correlation between tumor purity and immune function of gynecological cancers and its reliability as a prognostic indicator of immunotherapy. Gynecological cancer-related datasets were downloaded from The Cancer Genome Atlas (TCGA). Tumor purity was calculated by the ESTIMATE algorithm. A LASSO Cox regression analysis was performed to construct the risk score model. A Kaplan-Meier Plotter was used to explore the relationships between tumor purity and cancer prognosis. We performed the Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Set Enrichment Analysis (GSEA) to explore the pathways in the subgroups. A nomogram was used to quantitatively assess the cancer prognosis. Tumor purity was negatively correlated with B cell infiltration in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). Approximately 420 genes were positively associated with B cell infiltration and CESC prognosis and were enriched in immune-related signaling pathways. There were 11 key genes used to construct a risk score model. The low-risk group had a higher immune score and better prognosis than the high-risk group. A nomogram based on risk score, T stage, and clinical-stage had good predictive value in quantitatively evaluating CESC prognosis. This study is the first to reveal the correlation between tumor purity and immunity in CESC and suggests that low-risk patients may be more sensitive to immunotherapy. This provides a theoretical basis for the clinical treatment of CESC.

Identification of pyroptosis-related signature for cervical cancer predicting prognosis

Cervical cancer (CC) is one of the most common malignancies encountered in gynecology practice. However, there is a paucity of information about specific biomarkers that assist in the diagnosis and prognosis of CC. Pyroptosis is a form of programmed cell death whose different elements are related to the occurrence, invasion, and metastasis of tumors. However, the role of pyroptosis phenomena in the progression of CC has not yet been elucidated. This study focuses on the development of a pyroptosis-associated prognostic signature for CC using integrated bioinformatics to delineate the relationships among the signature, tumor microenvironment, and immune response of the patients. In this respect, we identified a prognostic signature that depends on eight pyroptosis-related genes (PRGs) that designate with better prognostic survival in the low-risk group (P<0.05) and where AUC values were greater than 0.7. A multi-factor Cox regression analysis indicated that such a signature could be used as an independent prognostic factor, and both the DCA and the Nomogram suggested that the proposed prognostic signature had good predictive capabilities. Interestingly, this prognostic signature can be applied to multiple tumors and thus, is versatile from a clinical point of view. In addition, there were significant differences in the tumor microenvironment and immune infiltration status between the high- and low-risk groups (P<0. 05). The core gene granzyme B (GZMB) was screened and the CC-associated regulatory axis, GZMB/ miR-378a/TRIM52-AS1, was constructed, which may promote CC progression, and further experimentation is needed to validate these results.

Machine learning constructs a T cell-related signature for predicting prognosis and drug sensitivity in ovarian cancer

The leading cause of death related to gynecologic cancer is ovarian cancer, which typically has a poor prognosis. T cells are referred to as key mediators of immunosurveillance and tumor eradication, and unbalanced regulation or lack of T cells in tumors result in immunotherapy resistance. The identification of T cell related markers depended on single-cell RNA-seq analysis. Using data from multiple datasets, including TCGA, GSE14764, GSE26193, GSE26712, and GSE140082, we constructed a prognostic signature called TRS (T cell-related signature) using 10 different machine learning algorithms. The correlation between TRS and drug sensitivity were analyzed using the data from GSE91061 and IMvigor210 dataset. PlsRcox method based TRS was as a risk factor for the clinical outcome of ovarian cancer patients. In comparison with stage, grade and many prognostic signatures, the performance of our TRS in evaluating the clinical outcome was better in ovarian cancer. TRS-based risk score showed distinct association with the level of ESTIMATE score, immune-related function score and immune cells. Moreover, TRS could be used to predict the immunotherapy response and chemotherapy response in ovarian cancer. In conclusion, we constructed a powerful TRS in ovarian cancer, which could accurately predict the clinical outcome of patients and be used to predict the immunotherapy response and chemotherapy response.

Prognostic role of long non-coding RNA USP30-AS1 in ovarian cancer: insights into immune cell infiltration in the tumor microenvironment

Ovarian cancer represents a formidable gynecologic malignancy bearing a dismal prognosis owing to the dearth of reliable early detection approaches and a high recurrence rate. Long non-coding RNAs (lncRNAs) have garnered immense attention as key orchestrators involved in diverse biological processes and take part in cancer initiation and progression. The present study investigated the potential significance of lncRNA USP30-AS1 in ovarian cancer prognosis, as well as its putative association with immune cell infiltration in tumor immune microenvironment (TIME). By analyzing publicly available datasets, we identified six lncRNAs with prognostic prediction ability, including USP30-AS1. The results revealed a significant positive correlation of USP30-AS1 expression with the infiltration of immune cells such as Th1 cells, TFH, CD8 T cells, B cells, antigen-presenting dendritic cells (aDC), and plasmacytoid dendritic cells (pDC) in ovarian cancer specimens. These findings provide compelling evidence of the potential involvement of lncRNA in the regulation of the TME in ovarian carcinoma. The outcomes from this study underscore the potential of USP30-AS1 as a promising prognostic biomarker for ovarian cancer. Additionally, the findings offer significant insights into the plausible role of lncRNAs in modulating immune activities, thus adding to our understanding of the disease biology. Additional investigations are necessary to unravel the molecular mechanisms underpinning these connections and validate the results seen in independent cohorts and experimental models.

Risk assessment of extra-uterine involvement and prognosis in young type I endometrial carcinoma with high or moderate differentiation and less than 1/2 myometrial invasion

The aim of this study was to investigate whether young patients with endometrial carcinoma can preserve adnexa and lymph nodes to improve their quality of life without compromising their prognosis. A total of 319 patients with type I endometrial carcinoma (high or moderate differentiation and less than 1/2 myometrial invasion) hospitalized in the First Affiliated Hospital of Zhengzhou University from May 2012 to July 2021 were included. The patients were divided into four groups: high differentiation without myometrial invasion group (G1MI-), high differentiation with superficial myometrial invasion group (G1MI+), moderate differentiation without myometrial invasion group (G2MI-), and moderate differentiation with superficial myometrial invasion group (G2MI+). Logistic regression analysis was conducted to identify risk factors for extra-uterine involvement. Kaplan-Meier method was used to draw the survival curve to compare the prognosis in subgroups and rates of extra-uterine involvement were also compared using Chi-square test or Fisher's exact test. Multivariable logistic regression revealed that differentiation (HR = 14.590, 95%CI = 1.778-119.754, Surgery with adnexal preservation and without systematic lymphadenectomy could be employed for the patients who are high differentiation with less than 1/2 myometrial invasion or moderate differentiation without myometrial invasion, but not recommended to the patients with moderate differentiation and superficial myometrial invasion.

Integrated bioinformatics data analysis reveals a risk signature and PKD1 induced progression in endometrial cancer patients with postmenopausal status

Endometrial cancer (EC) is one of the most common type of female genital malignancies. The purpose of the present study was to reveal the underlying oncogene and mechanism that played a pivotal role in postmenopausal EC patients. Weighted gene co-expression network analysis (WGCNA) was conducted using the microarray dataset and clinical data of EC patients from The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases to identify significant gene modules and hub genes associated with postmenopausal status in EC patients. LASSO regression was conducted to build and validate the risk model. Finally, expression of hub gene was validated in pre- and post-menopausal EC patients in our center. 1240 common genes were used to construct the WGCNA model. According to the WGCNA results, we identified a brown module with 471 genes which was significantly associated with postmenopausal status in EC patients. Furthermore, we constructed an 11-gene risk signature to predict the overall survival of EC patients. The Kaplan-Meier curve and area under the ROC curve (AUC) of this model showed high accuracy in prediction. We also validate the risk model in patients in our center and it also has a high accuracy. Among the 11 genes, PKD1 was recognized as a potential biomarker in the progression of EC patients with postmenopausal status. Taken together, we uncovered a common PKD1-mediated mechanism underlying postmenopausal EC patients' progression by integrated analyses. This finding may improve targeted therapy for EC patients.

Genomic mutation features identify distinct BRCA-associated mutation characteristics in endometrioid carcinoma and endometrioid ovarian carcinoma

Although endometrioid carcinoma (EC) and endometrioid ovarian carcinoma (EnOC) display similar pathological features, their molecular characteristics remain to be determined. Somatic mutation data from 2777 EC, 423 EnOC, and 57 endometriosis patients from the Catalogue of Somatic Mutations in Cancer (COSMIC) dataset were analyzed and showed similar profiles with different mutation frequencies among them. By using 275 overlapping mutated genes, EC was clustered into two groups with different disease outcomes and different clinical characteristics. Although BRCA-associated mutation characteristics were identified in both EC and EnOC, the mutation frequencies of BRCA1 (P=0.0146), BRCA2 (P=0.0321), ATR (P=3.25E-11), RAD51 (P=3.95E-08), RAD1 (P=0.0003), TP53 (P=6.11E-33), and BRIP1 (P=2.90E-09) were higher in EnOC. Further analysis showed that EnOC cell lines with BRCA-associated mutation characteristics were more sensitive to poly ADP-ribose polymerase (PARP) inhibitors than EC cell lines, including olaparib, talazoparib, rucaparib, and veliparib. Moreover, based on BRCA-associated mutational and transcriptomic profiles, EC with BRCA-associated mutational burdens shows lower levels of immune cell infiltration, higher expression of immunosuppressive checkpoint molecules and worse prognosis than EC without BRCA mutation. Our study comprehensively analyzed the genome mutation features of EC and EnOC and provide insights into the molecular characteristics of EC and EnOC.

Effect of age as a continuous variable in early-stage endometrial carcinoma: a multi-institutional analysis in China

To explore the effect of age at diagnosis as a continuous variable on survival and treatment choice of patients with early-stage endometrial carcinoma (EC). We retrospectively analyzed data from patients with early-stage EC from January 1999 to December 2015 in multiple institutions in China. All patients received primary hysterectomy/bilateral salpingo-oophorectomy and adjuvant radiotherapy for EC confirmed pathology of stage I and II disease (FIGO 2009 staging). All patients were divided into low-risk, intermediate-risk, high-intermediate-risk and high-risk groups according to ESMO-ESGO-ESTRO risk classification. The median follow-up time was 57months, and the 5-year cancer-specific survival (CSS) was 95.7%. Age as a continuous variable was an independent prognostic factor for CSS. With an increase in age, the hazard ratio (HR) for CSS increases gradually. Other independent prognostic factors included myometrial invasion (MI), grade, and chemotherapy. In the stratified analysis of age, the HRs of age on CSS in patients >70y were 5.516, 5.015, 4.469, 4.618, 5.334, and 5.821 after adjusting for cancer characteristics, local treatment, chemotherapy and treatment-related late toxicity. In patients 66-70-year-old, the HRs were 2.509, 2.074, 2.101, 2.091, 2.157 and 1.621 after adjusting for the above covariates. In patients ≤65y, there was no significant difference in the HR of age on CSS after adjustment. Age as a continuous variable is an independent prognostic factor and 65 year-old may be the best cut-off point for CSS in patients with early-stage EC in the Asian population. Quality of life should be given greater weight in the choice of therapeutic schedule for those patients >70 y.

Pan-cancer analysis and experimental validation revealed the m6A methyltransferase KIAA1429 as a potential biomarker for diagnosis, prognosis, and immunotherapy

KIAA1429, also known as VIRMA (vir-like m6A methyltransferase associated), plays a crucial role in tumorigenesis by modulating the level of m6A methylation. Previous studies have reported the prevalent overexpression of KIAA1429 in multiple cancers, related to a poor prognosis. Nevertheless, the precise role of KIAA1429 in tumor progression and its impact on the immune response remains unclear. A differential analysis of KIAA1429 expression was performed across cancers using data from the Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases. We evaluated the role of KIAA1429 in the diagnosis, prognosis, and immunotherapy of tumor patients using bioinformatics methods. In addition, we also analyzed the associations between KIAA1429 and DNA methylation, immunotherapy. RT-qPCR was used to study the expression levels of KIAA1429 mRNA in 11 cell lines. KIAA1429 is found to be overexpressed in 28 cancer types, but its expression is relatively low in patients with acute myeloid leukemia (LAML) and ovarian serous cystadenocarcinoma (OV). Moreover, KIAA1429 demonstrates a positive correlation with advanced stages of multiple cancers. Kaplan-Meier (KM) analysis suggested that patients with elevated KIAA1429 expression had shorter survival. Furthermore, KIAA1429 shows strong associations with DNA methylation, tumor-infiltrating immune cells (TIICs), and the tumor microenvironment (TME). RT-qPCR results indicated significantly higher expression of KIAA1429 in tumor cells compared to matched-normal cells. In summary, our work illustrates that KIAA1429 expression is positively connected with poor prognosis in multiple cancers. Moreover, KIAA1429 could serve as a diagnostic factor and a predictor of immune response for specific tumor types.

LIMK1 promotes the development of cervical cancer by up-regulating the ROS/Src-FAK/cofilin signaling pathway

In this study, we investigated the mechanism of action of LIMK1 in cervical cancer progression. The biological role of LIMK1 in regulating the growth, invasion, and metastasis of cervical cancer was studied in SiHa, CaSki cells and nude mice tumor models. The role of LIMK1 in the growth of cervical cancer was evaluated by HE staining. The role of LIMK1 in the invasion, metastasis, and proliferation of cervical cancer was evaluated by cell scratch, Transwell, and monoclonal experiments. The interaction among LIMK1, ROS, and Src was evaluated by Western blotting. The effects of regulating ROS and p-Src expression on LIMK1 in the migration/invasion and proliferation of cervical cancer cells were evaluated through cellular functional assays. Overexpression of LIMK1 promoted tumor growth in nude mice. Cell scratch, Transwell, and monoclonal experiments suggested that LIMK1 promoted the invasion, metastasis, and proliferation of cervical cancer cells. Western blotting suggested that LIMK1 can promote the expression of ROS-related proteins NOX2, NOX4, p-Src, and downstream proteins p-FAK, p-ROCK1/2, p-Cofilin-1, F-actin and inhibit the expression of p-SHP2 protein. Correction experiments showed that LIMK1 regulated the expression of p-FAK and p-Cofilin-1 proteins by regulating ROS and p-Src. Through the detection of cervical cancer cell functions, it was found that the activation of ROS and p-Src induced by LIMK1 is an early event that promotes the migration, proliferation, and invasion of cervical cancer cells. LIMK1 promotes the expression of F-actin and promotes the development of cervical cancer by regulating the oxidative stress/Src-mediated p-FAK/p-ROCK1/2/p-Cofilin-1 pathway.

Development and validation of a novel anoikis-related gene signature for predicting prognosis in ovarian cancer

Anoikis plays a critical role in variable cancer types. However, studies that focus on the prognostic values of anoikis-related genes (ANRGs) in OV are scarce. Cohorts with transcriptome data and corresponding clinicopathologic data of OV patients were collected and consolidated from public databases. Multiple bioinformatics approaches were used to screen key genes from 446 anoikis-related genes, including Cox regression analysis, random survival forest analysis, and Kaplan-Meier analysis of best combinations. A five-gene signature was constructed in the discovery cohort (TCGA) and validated in four validation cohorts (GEO). Risk score of the signature stratified patients into high-risk (HRisk) and low-risk (LRisk) subgroups. Patients in the HRisk group were associated with worse OS than those in the LRisk group in both the TCGA cohort (p<0.0001, HR=2.718, 95%CI:1.872-3.947) and the four GEO cohorts (p<0.05). Multivariate Cox regression analyses confirmed that the risk score served as an independent prognostic factor in both cohorts. The signature's predictive capacity was further demonstrated by the nomogram analysis. Pathway enrichment analysis revealed that immunosuppressive and malignant progression-related pathways were enriched in the HRisk group, including TGF-β, WNT and ECM pathways. The LRisk group was characterized by immune-active signaling pathways (interferon-gamma, T cell activation, etc.) and higher proportions of anti-tumor immune cells (NK, M1, etc.) while HRisk patients were associated with higher stromal scores and less TCR richness. In conclusion, the signature reveals a close relationship between the anoikis and prognosis and may provide a potential therapeutic target for OV patients.

Inhibition of apoptosis through AKT-mTOR pathway in ovarian cancer and renal cancer

Ovarian cancer and renal cancer are malignant tumors; however, the relationship between TTK Protein Kinase (TTK), AKT-mTOR pathway and ovarian cancer, renal cancer remains unclear. Download GSE36668 and GSE69428 from Gene Expression Omnibus (GEO) database. Weighted gene co-expression network analysis (WGCNA) was performed. Created protein-protein interaction (PPI) network. Used Gene Ontology analysis (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) for functional enrichment analysis. Gene Set Enrichment Analysis (GSEA) analysis and survival analysis were performed. Created animal model for western blot analysis. Gene Expression Profiling Interactive Analysis (GEPIA) was performed to explore the role of TTK on the overall survival of renal cancer. GO showed that DEGs were enriched in anion and small molecule binding, and DNA methylation. KEGG analysis presented that they mostly enriched in cholesterol metabolism, type 1 diabetes, sphingolipid metabolism, ABC transporters, etc., TTK, mTOR, p-mTOR, AKT, p-AKT, 4EBP1, p-4EBP1 and Bcl-2 are highly expressed in ovarian cancer, Bax, Caspase3 are lowly expressed in ovarian cancer, cell apoptosis is inhibited, leading to deterioration of ovarian cancer. Furthermore, the TTK was not only the hub biomarker of ovarian cancer, but also one significant hub gene of renal cancer, and its expression was up-regulated in the renal cancer. Compared with the renal cancer patients with low expression of TTK, the patients with high expression of TTK have the poor overall survival ( TTK inhibits apoptosis through AKT-mTOR pathway, worsening ovarian cancer. And TTK was also one significant hub biomarker of renal cancer.

Analysis of cancer-associated fibroblasts in cervical cancer by single-cell RNA sequencing

Since scRNA-seq is an effective tool to study tumor heterogeneity, this paper intends to reveal the differences of cervical cancer in patients at the individual cell level by scRNA-seq, and focus on the biological functions of cancer-associated fibroblasts (CAFs) in cervical cancer, facilitating the provision of a new interpretation of the heterogeneity of the microenvironment of cervical cancer, and an in-depth exploration of the pathogenesis of cervical cancer as well as pursuit of effective means of treatment intake. 3 cervical cancer specimens were collected by clinical surgery for single-cell RNA sequencing. Cell suspensions of fresh cervical cancer tissues were prepared, and cDNA libraries were created and sequenced on the machine. Furthermore, the sequencing data were analyzed using bioinformatics, including descending clustering of cells, identification of cell populations, mimetic time series analysis, inferCNV, cell communication analysis, and identification of transcription factors. A total of 9 cell types were identified, encompassing T cells, epithelial cells, smooth muscle cells, CAFs, endothelial cells, macrophages, B cells, lymphocytes, and plasma cells. CAFs were further divided into three cell subtypes, named type1 cells, type2 cells, and type3 cells. With key transcription factors for the three cells, TCF21, ZC3H11A, and MYEF2 obtained, this research revealed the communication relationship between CAFs and several other cells, and found an important role of CAFs in the MK signaling pathway. scRNA-seq technology contributed to exploring the tumor heterogeneity of cervical cancer more deeply, and also further gaining insight into the biological functions of CAFs in cervical cancer.

Immune landscape and heterogeneity of cervical squamous cell carcinoma and adenocarcinoma

Despite the differences in disease outcomes and pathological features between cervical squamous cell carcinoma (CSCC) and adenocarcinoma (ADC), the molecular characteristics in immune heterogeneity of the tumor microenvironment remain unclear. Here, we explored the immune landscape and heterogeneity between CSCC and ADC. Gene expression and clinical characteristics of cervical carcinoma from The Cancer Genome Atlas (TCGA) were downloaded. Differentially expressed genes (DEGs), immune cell infiltration, and pathway enrichment analyses were used to explore the immune landscape and heterogeneity between CSCC and ADC. Furthermore, distinct immune signatures between CSCC and ADC were validated based on clinical samples. In total, 4,132 upregulated DEGs and 2,307 down-regulated DEGs were identified between CSCC and ADC, with enrichments in immune related-pathways in CSCC. In addition, 54 hub DEGs correlated with patients' prognosis and immunocytes infiltration were identified. The CSCC patients had a higher ImmuneScore and more abundant immunocytes infiltration compared to ADC patients, as validated by immunohistochemistry (IHC) and multicolor immunofluorescence (mIF) analyses of collected samples. Furthermore, CSCC displayed higher inhibitory immune checkpoints expression, tumor mutation burden (TMB), and microsatellite instability (MSI) compared to ADC, which indicated CSCC patients were more likely to benefit from immunotherapy. In summary, our results revealed the huge immune heterogeneity between CSCC and ADC, and provided guidance for immunotherapy selection for different pathological types of cervical cancer.

Comprehensive analysis of ZNF692 as a potential biomarker associated with immune infiltration in a pan cancer analysis and validation in hepatocellular carcinoma

Currently, the roles of ZNF692 have been documented exclusively in lung, colon, and cervical cancers. However, its involvement in pan cancer remains unknown. In this study, we employed bioinformatics analysis and experimental validation to investigate the role of ZNF692 in pan cancer. Our findings revealed aberrant expression of ZNF692 across various types of cancer. High expression of ZNF692 was associated with poor overall survival (OS) in ACC, COAD, KIRC, LAML, and LIHC. ZNF692 exhibited promising diagnostic potential in certain tumor types. A significant correlation was observed between high ZNF692 expression and advanced stages of ACC, BLCA, KICH, KIRC, LIHC, and OV. The expression of ZNF692 exhibited a significant association with microsatellite instability (MSI) in eight types of cancer and tumor mutational burden (TMB) in ten types of cancer. A noteworthy correlation was observed between ZNF692 expression and immune infiltration as well as immune checkpoints. Amplification of ZNF692 emerged as the most frequent alteration in pan cancer. ZNF692 was implicated in various biological processes, cellular components, and molecular functions within the context of pan cancer. It is plausible that ZNF692 may contribute to chemotherapy and potentially be linked to chemoresistance. We constructed a competing endogenous RNA (ceRNA) network involving AC009403.11/miR-126-3p/ZNF692 in hepatocellular carcinoma (HCC). The expression of ZNF692 exhibited a notable upregulation in HCC cell lines. Aberrant expression of ZNF692 was observed across various types of cancer. ZNF692 holds potential as a valuable diagnostic, prognostic, and therapeutic target in the context of pan cancer.

A cellular senescence-related genes model allows for prognosis and treatment stratification of cervical cancer: a bioinformatics analysis and external verification

Cervical cancer (CC) is highly lethal and aggressive with an increasing trend of mortality for females. Molecular characterization-based methods hold great promise for improving the diagnostic accuracy and for predicting treatment response. The mRNAs expression data of CC patients and cellular senescence-related genes were obtained from the Cancer Genome Atlas (TCGA) and CellAge databases, respectively. Differentially expressed genes (DEGs) of senescence related genes between tumor and normal tissues were used for Least absolute shrinkage and selection operator (LASSO) regression to construct a prognostic model. Univariate and LASSO regression analyses were applied to establish a predictive nomogram. The performance of the nomogram were evaluated by Kaplan-Meier curve, receiver operating characteristic (ROC), Harrell's concordance index (C-index), and calibration curve. GSE44001 and GSE52903 were used for external validation. We established a cellular senescence-related genes-based stratified model, and a multivariable-based nomogram, which could accurately predict the prognosis of CC patients in the TCGA database. The Kaplan-Meier curve indicated that patients in the low-risk group had considerably better overall survival (OS, Our results suggested a six-senescence related signature and established a prognostic nomogram that reliably predicted the overall survival for CC. These findings may be beneficial to personalized treatment and medical decision-making.

Improving ovarian cancer treatment decision using a novel risk predictive tool

As a major component of the tumor tissue, the tumor microenvironment (TME) has been proven to associate with tumor progression and immunotherapy. Ovarian cancer accounts for the highest mortality rate among gynecologic malignancies. Its clinical treatment decision is highly correlated with the prognosis, underscoring the need to evaluate the prognosis and choose the proper clinical treatment through TME information. This study constructs a score with TME information obtained by the CIBERSORT algorithm, which classifies the patients into high and low TMEscore groups with quantified TME infiltration patterns through the PCA algorithm. TMEscore was constructed by TCGA cohort and validated in GEO cohort. Univariate and multivariate Cox proportional hazards model analyses were used to demonstrate prognostic value of TMEscore in overall and stratified analysis. TMEscore is highly correlated with survival and high TMEscore group has a better prognosis. In order to improve treatment decision, the expression of immune checkpoints, immunophenoscore (IPS) and ESTIMATE score showed a high TMEscore have a better immune microenvironment and respond better to immune checkpoint inhibitors (ICIs). Meanwhile, the mutation landscape between TMEscore groups was profiled, and 13 genes were found mutated differently between the two groups. Among them, BRCA1 has more mutations in the high TMEscore group and speculated that high TMEscore patients might be a beneficiary population of PARP inhibitors combined with immunotherapy. TMEscore based on TME with prognostic value and clinical value is proposed for the identification of targets treatment and immunotherapy strategies for ovarian cancer.

Highly expressed STAT1 contributes to the suppression of stemness properties in human paclitaxel-resistant ovarian cancer cells

Signal transducer and activator of transcription-1 (STAT1) is an important factor in various cellular processes. The cancer stem cell (CSC) is considered as a tumor-initiating cell that drives the inner hierarchy in many cancers including epithelial ovarian cancer (EOC). Here, we explored for the first time the regulation of STAT1 on stemness properties in chemoresistant EOC cells. The paclitaxel (PTX)-resistant EOC cell line (OV3R-PTX) was derived from PTX-sensitive OVCAR-3 cells treated by the PTX regimen. A single cell clone OV3R-PTX-B4 was selected by fluorescence-activated cell sorting. PTX-resistant cells grew slowly in conventional 2D and 3D cultures, but tumor xenograft with PTX-resistant cells grew fast in nude mice. Interestingly, OV3R-PTX-B4 cells shared the characteristics of CSCs and stemness properties were found to be increased in the non-adherent spheroid culture system. The PTX-resistant cells had a high expression of CSC-related markers and low expression of STAT1 that had a high methylation level of CpG in its promoter region. Overexpressed STAT1 suppressed stemness properties, cell proliferation, and colony formation and favored the overall survival of patients with EOC. In summary, these data indicate a regulatory mechanism of STAT1 underlying drug resistance and provide a potential therapeutic application for EOC patients with PTX resistance.

Prognostic value of prostaglandin I2 synthase and its correlation with tumor-infiltrating immune cells in lung cancer, ovarian cancer, and gastric cancer

Prostaglandin I2 synthase (PTGIS) is a crucial gene for the synthesis of prostaglandin I2, which has multiple roles in inflammation and immune modulation. However, studies on the prognostic value of PTGIS and its correlation with tumor-infiltrating immune cells in multiple cancers are still rare. Multiple datasets of the Oncomine database showed that PTGIS was expressed at low levels in lung cancer and ovarian cancer compared to the levels in normal tissues. Kaplan-Meier plotter showed that high PTGIS was associated with poor overall survival and progression-free survival in lung, ovarian, and gastric cancers. Moreover, PTGIS expression was significantly positively correlated with infiltrating levels of macrophages and was strongly associated with a variety of immune markers, especially tumor-associated macrophages (TAMs) and T-regulatory cells (Tregs). High expression of PTGIS could promote the infiltration of TAMs and Tregs in the tumor microenvironment and deteriorate outcomes of patients with lung, ovarian, and gastric cancers. These findings suggest that PTGIS could be taken as a potential biomarker of prognosis and tumor-infiltrating immune cells. PTGIS expression was investigated in different datasets of the Oncomine database, and its expression levels in various tumors and corresponding normal tissues were analyzed by the Tumor Immune Estimation Resource (TIMER). Then, the clinical prognostic value of PTGIS was assessed with online public databases. In addition, we initially explored the correlation between PTGIS and tumor-infiltrating immune cells by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA).

LDH-A inhibitors as remedies to enhance the anticancer effects of PARP inhibitors in ovarian cancer cells

Ovarian cancer is one of the most lethal gynecologic malignancies. It has been shown that PARP inhibitors can selectively target BRCA-mutated ovarian cancer and exert some effects on ovarian cancer without BRCA mutations. However, the mechanism is still unclear. In this study, wild-type BRCA ovarian cancer cells (A2780 and SKOV3) were used. Our results showed that using a PARP inhibitor (olaparib or AG14361) alone significantly inhibited the proliferation of A2780 cells but negligibly inhibited the proliferation of SKOV3 cells. We used RNA sequencing to explore differentially expressed genes and found that PARP inhibitors increased LDH-A in SKOV3 cells, which was confirmed by RT-PCR. Oxamate (a specific inhibitor of LDH-A) was used to investigate whether LDH-A inhibition enhances the suppressive effects of PARP inhibitors on ovarian cancer without BRCA mutations. CCK-8 assays, scratch assays and Transwell assays were used to determine cell proliferation, cell migration ability and invasion ability, respectively. Both olaparib and AG14361 significantly inhibited the proliferation/invasion ability of A2780 cells but not SKOV3 cells. Inhibition of LDH-A can remarkably promote the inhibitory effects of PARP inhibitors on both A2780 and SKOV3 cells. Thus, high expression level of LDH-A influenced the suppressive effects of PARP inhibitors on ovarian cancer with wild-type BRCA, and LDH-A inhibition notably enhanced this effect.

The risk of distant metastases in patients with gynecologic cancers after surgery: a population-based study

The aim of the study was to determine the risk of distant metastases in patients with gynecologic cancers after surgery, including cervical, uterine and ovarian cancers. This is a retrospective study evaluating gynecologic cancer from 2009 to 2014 using population-based administrative datasets from the Health and Welfare Data Science Center (HWDC) and from The National Health Informatics Project (NHIP). A total of 1,464 gynecologic cancer patients, including 321 cervical cancer patients, 724 uterine cancer patients and 419 ovarian cancer patients, were analyzed retrospectively from 2009 to 2014. Among the cervical cancer patients, 173 (53.89%) received surgery only and 148 (46.11%) received surgery with radiotherapy /chemotherapy. Among the uterus cancer patients, 425(58.70%) received surgery only and 299 (41.3%) received surgery with radiotherapy /chemotherapy. Among the ovarian cancer patients, 81 (19.33%) received surgery only and 338 (80.67%) received surgery with radiotherapy/chemotherapy. Among patients with brain, liver or lung metastasis, cervical cancer patients have more cumulative metastasis-free survival than those ovarian cancer (p=0.0041). In analyzing liver metastasis based on primary cancer sites, cervical cancer patients and uterine cancer cases have more cumulative metastasis- free survival than those ovarian cancer (p<0.0001). In conclusion, ovarian cancer patients have higher risk of liver metastasis than cervical or uterine cancer. There were significantly different of pathological stage for cumulative metastasis-free survival among gynecologic cancer patients with brain or liver or lung metastasis. Pathological T stage remains the main predictive for distant metastasis of gynecologic cancer.

Antiparasitic mebendazole (MBZ) effectively overcomes cisplatin resistance in human ovarian cancer cells by inhibiting multiple cancer-associated signaling pathways

Ovarian cancer is the third most common cancer and the second most common cause of gynecologic cancer death in women. Its routine clinical management includes surgical resection and systemic therapy with chemotherapeutics. While the first-line systemic therapy requires the combined use of platinum-based agents and paclitaxel, many ovarian cancer patients have recurrence and eventually succumb to chemoresistance. Thus, it is imperative to develop new strategies to overcome recurrence and chemoresistance of ovarian cancer. Repurposing previously-approved drugs is a cost-effective strategy for cancer drug discovery. The antiparasitic drug mebendazole (MBZ) is one of the most promising drugs with repurposing potential. Here, we investigate whether MBZ can overcome cisplatin resistance and sensitize chemoresistant ovarian cancer cells to cisplatin. We first established and characterized two stable and robust cisplatin-resistant (CR) human ovarian cancer lines and demonstrated that MBZ markedly inhibited cell proliferation, suppressed cell wounding healing/migration, and induced apoptosis in both parental and CR cells at low micromole range. Mechanistically, MBZ was revealed to inhibit multiple cancer-related signal pathways including ELK/SRF, NFKB, MYC/MAX, and E2F/DP1 in cisplatin-resistant ovarian cancer cells. We further showed that MBZ synergized with cisplatin to suppress cell proliferation, induce cell apoptosis, and blunt tumor growth in xenograft tumor model of human cisplatin-resistant ovarian cancer cells. Collectively, our findings suggest that MBZ may be repurposed as a synergistic sensitizer of cisplatin in treating chemoresistant human ovarian cancer, which warrants further clinical studies.

A novel prognostic signature based on cancer stemness and metabolism-related genes for cervical squamous cell carcinoma and endocervical adenocarcinoma

CESC is the second most commonly diagnosed gynecological malignancy. Given the pivotal involvement of metabolism-related genes (MRGs) in the etiology of multiple tumors, our investigation aims to devise a prognostic risk signature rooted in cancer stemness and metabolism. The stemness index based on mRNA expression (mRNAsi) of samples from the TCGA dataset was computed using the One-class logistic regression (OCLR) algorithm. Furthermore, potential metabolism-related genes related to mRNAsi were identified through weighted gene co-expression network analysis (WGCNA). We construct a stemness-related metabolic gene signature through shrinkage estimation and univariate analysis, thereby calculating the corresponding risk scores. Moreover, we selected corresponding DEGs between groups with high- and low-risk score and conducted routine bioinformatic analyses. Furthermore, we validated the expression of four hub genes at the protein level through immunohistochemistry (IHC) in samples obtained from our patient cohort. According to the findings, it was found that six genes-AKR1B10, GNA15, ALDH1B1, PLOD2, LPCAT1, and GPX8- were differentially expressed in both TCGA-CSEC and GEO datasets among 23 differentially expressed metabolism-related genes (DEMRGs). mRNAsi exhibited a notable association with the extent of key oncogene mutation. The results showed that the AUC values for forecasting survival at 1, 3, and 5 years are 0.715, 0.689, and 0.748, individually. We observed a notable association between the risk score and different immune cell populations, along with enrichment in crucial signaling pathways in CESC. Four genes differentially expressed between different risk score groups were validated by IHC to be highly expressed in the CESC samples at the protein level. The current investigation indicated that a 3-gene signature based on stemness-related metabolic and 4 hub genes with differential expression between high and low-risk score subgroups may serve as valuable prognostic markers and potential therapeutic targets in CESC.

Interference with ANXA8 inhibits the malignant progression of ovarian cancer by suppressing the activation of the Wnt/β-catenin signaling pathway via UCHL5

Ovarian cancer (OC), which threatens women's lives, is a common tumor of the female reproductive system. Annexin A8 (ANXA8) is highly expressed in OC. However, the mechanism of ANXA8 in OC remains unclear. This study investigated the potential mechanisms of ANXA8 in OC. The expression of ANXA8 in OC cells was determined by qRT-PCR and western blotting. ANXA8 interference plasmid was constructed. Moreover, CCK-8, EDU staining, TUNEL staining, western blotting, wound healing, and transwell assays were used to detect cell proliferation, apoptosis, migration, and invasion, respectively. Next, the relationship between ANXA8 and ubiquitin C-terminal hydrolase L5 (UCHL5) was verified through Co-IP. Finally, western blotting was used to detect the expression of Wnt/β-catenin signaling-related proteins. Additionally, we further interfered ANXA8 in nude mice with OC, and detected the expression of ANXA8, UCHL5 and the signaling pathway-related proteins by immunohistochemistry and western blotting. Our results suggested that ANXA8 expression was significantly increased in OC cells. ANXA8 interference significantly attenuated the proliferative, invasive, and migratory capabilities and promoted the apoptotic ability of OC cells. Moreover, the expression of UCHL5 in OC was significantly increased. ANXA8 bound to UCHL5 in OC cells. Knockdown of ANXA8 attenuated OC cell malignant progression by downregulating the expression of UCHL5. Furthermore, ANXA8 affected the expression of Wnt/β-catenin signaling pathway-related proteins in OC cells via UCHL5. Collectively, ANXA8 interference suppressed the activation of Wnt/β-catenin signaling pathway via UCHL5 to inhibit cell proliferation, invasion, migration and induce cell apoptosis in OC, thus presenting a potential therapeutic strategy for OC treatment.

Signatures of tumor-associated macrophages correlate with treatment response in ovarian cancer patients

Ovarian cancer (OC) ranks as the second leading cause of death among gynecological cancers. Numerous studies have indicated a correlation between the tumor microenvironment (TME) and the clinical response to treatment in OC patients. Tumor-associated macrophages (TAMs), a crucial component of the TME, exert influence on invasion, metastasis, and recurrence in OC patients. To delve deeper into the role of TAMs in OC, this study conducted an extensive analysis of single-cell data from OC patients. The aim is to develop a new risk score (RS) to characterize the response to treatment in OC patients to inform clinical treatment. We first identified TAM-associated genes (TAMGs) in OC patients and examined the protein and mRNA expression levels of TAMGs by Western blot and PCR experiments. Additionally, a scoring system for TAMGs was constructed, successfully categorizing patients into high and low RS subgroups. Remarkably, significant disparities were observed in immune cell infiltration and immunotherapy response between the high and low RS subgroups. The findings revealed that patients in the high RS group had a poorer prognosis but displayed greater sensitivity to immunotherapy. Another important finding was that patients in the high RS subgroup had a higher IC50 for chemotherapeutic agents. Furthermore, further experimental investigations led to the discovery that THEMIS2 could serve as a potential target in OC patients and is associated with EMT (epithelial-mesenchymal transition). Overall, the TAMGs-based scoring system holds promise for screening patients who would benefit from therapy and provides valuable information for the clinical treatment of OC.

Machine learning developed a PI3K/Akt pathway-related signature for predicting prognosis and drug sensitivity in ovarian cancer

Ovarian cancer is one of the deadliest malignancies among females, generally having a poor prognosis. The PI3K/Akt pathway plays a vital role in the oncogenesis and progression of many types of cancer. Limited studies have fully clarified the role of PI3K/Akt pathway in the prognosis of ovarian cancer and its correlation with drug sensitivity. A prognostic PI3K/Akt pathway related signature (PRS) was constructed with 10 machine learning algorithms using TCGA, GSE14764, GSE26193, GSE26712, GSE63885 and GSE140082 datasets. Gaussian mixture and logistic regression were performed to identify the optimal models for classifying lymphatic and venous invasion. The optimal prognostic PRS developed by Lasso + survivalSVM algorithm acted as an independent risk factor for overall survival (OS) of ovarian cancer patients and had a good performance in evaluating OS rate of ovarian cancer patients. Significant correlation was obtained between PRS-based risk score and Immune score, ESTIMATE score, immune cells and cancer-related hallmarks. Low risk score indicated a lower immune escape score, TIDE score, and higher PD1&CTLA4 immunophenoscore in ovarian cancer. Moreover, PRS-based risk score acted as an indicator for drug sensitivity in the immunotherapy and chemotherapy of ovarian cancer patients. All in all, our study developed a prognostic PRS showing powerful and good performance in predicting clinical outcome of ovarian cancer patients. PRS could serve as an indicator for drug sensitivity in the chemotherapy and immunotherapy.

Defining three ferroptosis-based molecular subtypes and developing a prognostic risk model for high-grade serous ovarian cancer

As a newly defined regulated cell death, ferroptosis is a potential biomarker in ovarian cancer (OV). However, its underlying mechanism in tumor microenvironment (TME) and clinical prediction significance in OV remained to be elucidated. The transcriptome data of high-grade serous OV from The Cancer Genome Atlas (TCGA) database were downloaded. Molecular subtypes were classified based on ferroptosis-correlated genes from the FerrDb database by performing consensus clustering analysis. The associations between the subtypes and clinicopathologic characteristics, mutation, regulatory pathways and immune landscape were assessed. A ferroptosis-related prognostic model was constructed and verified using International Cancer Genome Consortium (ICGC) cohort and GSE70769. Three molecular subtypes of OV were defined. Patients in subtype C3 tended to have the most favorable prognosis, while subtype C1 showing more mesenchymal cells, increased immune infiltration of Macrophages_M2, lower tumor purity, and epithelial-to-mesenchymal transition (EMT) features had the poorest prognosis. A ferroptosis-related risk model was constructed using 8 genes (PDP1, FCGBP, EPHA4, GAS1, SLC7A11, BLOC1S1, SPOCK2, and CXCL9) and manifested a strong prediction performance. High-risk patients had enriched EMT pathways, more Macrophages_M2, less plasma cells and CD8 cell infiltration, greater tendency of immune escape and worse prognosis. The risk score has negatively correlated relation with LAG3, TIGIT, CTLA4, IDO1, CD27, ICOS, and IL2RB but positively correlated with PVR, CD276, and CD28. Moreover, low-risk patients were more sensitive to Cisplatin and Gefitinib, Gemcitabine. Our results could improve the understanding of ferroptosis in OV, providing promising insights for the clinical targeted therapy for the cancer.

ERR&amp;#x3B1; acts as a potential agonist of PPAR&amp;#x3B3; to induce cell apoptosis and inhibit cell proliferation in endometrial cancer

Two transcriptional factors, peroxisome proliferator-activated receptor-γ (PPARγ) and estrogen-related receptor-α (ERRα), have been reported to be key regulators of cellular energy metabolism. However, the relationship between ERRα and PPARγ in the development of endometrial cancer (EC) is still unclear. The expression levels of PPARγ and ERRα in EC were evaluated by quantitative real-time PCR, western blot, tissue array and immunohistochemistry. A significant negative correlation was identified between PPARγ and ERRα expression in women with EC (ρ=-0.509, P<0.001). Bioinformatics analyses showed that PPARγ and ERRα can activate or inhibit the same genes involved in cell proliferation and apoptosis through a similar ModFit. ERRα activation or PPARγ inhibition could promote proliferation and inhibit apoptosis through the Bcl-2/Caspase3 pathways. Both PPARγ and ERRα can serve as serum tumor markers. Surprisingly, as evaluated by receiver operating characteristic (ROC) curves and a logistic model, a PPARγ/ERRα ratio≤1.86 (area under the ROC curve (AUC)=0.915, Youden index=0.6633, P<0.001) was an independent risk factor for endometrial carcinogenesis (OR=14.847, 95% CI= 1.6-137.748, P=0.018). EC patients with PPARγ(-)/ERRα(+) had the worst overall survival and disease-free survival rates (both P<0.001). Thus, a dynamic imbalance between PPARγ and ERRα leads to endometrial carcinogenesis and predicts the EC prognosis.

Publisher

Impact Journals, LLC

ISSN

1945-4589