Ovarian mature teratoma (OT) is a common ovarian germ cell tumor, and its early onset, multifocality, recurrence and familial aggregation suggest that genetic susceptibility contributes to a subset of cases. Whole-exome sequencing was used to identify candidate susceptibility variants in a family with recurrent and multifocal OT. A rare heterozygous germline TXNIP variant, NM_006472.6:c.1049C>T (p.Pro350Leu), was identified and confirmed by Sanger sequencing. p.Pro350Leu TXNIP showed lower steady-state abundance, faster cycloheximide-chase decay, and greater K48-linked polyubiquitination than wild-type TXNIP. Familial OT specimens also showed weaker TXNIP staining and stronger GLUT1 staining than sporadic OT specimens. TXNIP depletion increased plasma-membrane GLUT1, glucose uptake, lactate production and hyperactivated the PI3K/mTOR pathway, and familial tissues reproduced this PI3K/mTOR-dominant state. To our knowledge, this is the first genomic and functional investigation of a germline susceptibility mechanism for human familial ovarian mature teratoma. These findings establish TXNIP as the first functional candidate susceptibility gene for this phenotype and connect inherited susceptibility to ubiquitin-dependent protein turnover, GLUT1-driven metabolic reprogramming, and PI3K/mTOR-dominant follicular signaling.

To explore the effect of preoperative conization on the prognosis of patients with stage IB1 (FIGO 2018) cervical cancer and to compare the prognosis between laparoscopic radical hysterectomy (LRH) and abdominal radical hysterectomy (ARH) following conization. This multicentre, retrospective, case-paired cohort study compared the 5-year overall survival (OS) and disease-free survival (DFS) between the conization group and the non-conization group under the condition of propensity score matching. Further subgroup analysis was conducted to compare OS and DFS between laparoscopic surgery and abdominal surgery after conization. A total of 1319 patients with stage IB1 cervical cancer were included in this study, and there was no significant difference in oncological prognosis between the conization group (n = 383) and the non-conization group (n = 936) (OS: 94.3

Background:The current standard-of-care chemotherapy for treatment-naïve epithelial ovarian cancer is paclitaxel plus carboplatin. Objectives:To compare the efficacy and safety of pegylated liposomal doxorubicin (PLD) plus carboplatin versus paclitaxel plus carboplatin as first-line treatment in patients with epithelial ovarian cancer. Design:This was an investigator-initiated, multicenter, open-label, randomized, noninferiority trial. Methods:This trial with a prespecified noninferiority margin (HR0) of 1.2, was conducted in 20 clinic centers in China. Eligible patients were randomly assigned in a 1:1 ratio to receive either PLD (30 mg/m2 on day 1) plus carboplatin (area under the curve (AUC) 5 on day 1; experimental group) or paclitaxel (175 mg/m2 on day 1) plus carboplatin (AUC 5 on day 1; control group) for up to six cycles. The primary endpoint was progression-free survival (PFS). The key secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and safety. Results:Between March 21, 2019, and December 8, 2021, 395 eligible patients were enrolled, of whom 195 were randomly assigned to receive PLD-carboplatin and 196 received paclitaxel-carboplatin. Median PFS was 35.3 months (95% confidence interval (CI), 23.7-46.9) in the experimental group and 35.0 months (95% CI, 26.9-43.1) in the control group (hazard ratio = 0.99, 95% CI, 0.73-1.35; p = 0.94). There were no statistically significant differences between the two groups in median ORR (80.5% vs 79.2%), DCR (90.2% vs 83.3%), 2-year OS rate (96.2% vs 92.4%), or 4-year OS rate (87.6% vs 82.4%; all p > 0.05). In the experimental and control groups, 165 (84.6%) and 169 (86.2%) patients experienced at least one adverse event (AEs). Alopecia (9.2% vs 28.1%, p < 0.001), peripheral sensory neuropathy (2.1% vs 17.9%, p < 0.001), and febrile neutropenia (1.0% vs 6.1%, p = 0.01) were less common in the PLD-carboplatin group compared to the paclitaxel-carboplatin group. Conclusion:The superior tolerability and comparable efficacy of PLD plus carboplatin over paclitaxel plus carboplatin as a first-line treatment for epithelial ovarian cancer suggest that substituting paclitaxel with PLD is both feasible and potentially more beneficial. Trial registration:This trial is registered with ClinicalTrials.gov, NCT03794778.

Background: Immature teratoma is a malignant tumor and accounts for 1%-3% of ovary teratoma. The objective of this study was to find the potential single nucleotide polymorphisms (SNPs), copy number variations (CNVs) and drug targets in the immature teratoma. Material and Methods: Genomic DNA was extracted from peripheral blood of 26 sporadic immature teratoma patients for whole exome sequencing (WES) analysis to detect germline variants. SNPs and CNVs were identified, followed by the analysis of physical/ chemical properties and conserved domain of mutated genes. Functional enrichment and protein-protein interaction (PPI) analysis of mutated genes was performed, followed by pharmacogenomic analysis. Finally, SNPs, CNVs and mRNA expression of mutated genes were investigated in ovarian cancer by using the online databases. Results: A total of 24 common mutated genes were identified in 26 patients. Among which, 5 common mutated genes with common mutation sites were identified, including 2 frameshift mutant genes (MYPOP and FRG2C) and 3 nonsynonymous mutant genes (CNTNAP3, GPRIN2 and MUC3A). After mutation, molecular weight of MYPOP, FRG2C, CNTNAP3, GPRIN2 and MUC3A changed slightly. In the PPI network, MUC12 (with the highest degree) interacted with GALNT12, MUC3A and FCGBP. Based on the pharmacogenomic analysis, MUC2 was predicted to be a potential drug target of CHEMBL35482, FLUOROURACIL and DECITABINE. According to the functional analysis, MUC3A, MUC2 and MUC12 were involved in biological processes of activation of the innate immune response. The mutation frequency of FCGBP and CNTNAP3 was rare and had a higher amplification frequency in ovarian cancer. In addition, 2 common CNVs (deletion state) were screened out, which involving 6 genes, such as RP11. Conclusion: This study identified some potential SNPs and CNVs, which may contribute to clarifying the pathogenesis of immature teratoma and provide potential biomarkers and drug targets for this disease.

We previously identified the germline mutation c.262C > T in BMP15 as a genetic susceptibility factor of hereditary ovarian immature teratoma (OIT). However, not all female carriers in that family had OIT. In this study, we analyzed the genetic differences among these individuals, aiming to explore whether any genes may be copathogenic with BMP15. The subjects were recruited from two three-generation pedigrees of hereditary OIT. Whole-exome sequencing (WES) was performed, and the candidate variants were subsequently tested by Sanger sequencing. Moreover, bioinformatics was used to assess the mutation with MutationTaster and Combined Annotation Dependent Depletion (CADD), and pathogenicity was predicted according to the American College of Medical Genetics and Genomics (ACMG) guidelines. The effect of the mutation on CDHR2 expression was evaluated by RT-qPCR, Western blotting, and immunofluorescence with confocal microscopy. WES revealed that, unlike the two unaffected sisters, both affected second-generation individuals harbored a germline mutation in CDHR2 (c.2233C > T, p.R745X) in addition to the mutation in BMP15 (c.262C > T, p.R86C). CDHR2 c.2233C > T is a truncating mutation that was predicted to be deleterious by MutationTaster and CADD and classified as pathogenic according to the ACMG criteria. Our in vitro experiments revealed that mRNA and protein expression levels were significantly lower in cells with the 2233T allele than in those with the 2233C allele. Moreover, the localization of the mutant product in cells was significantly different from that of the wild-type protein. The mutant group exhibited abnormal accumulation of small-molecule metabolites, along with aberrant activation of the HIPPO signaling cascade. Our findings suggest that the CDHR2 c.2233C > T variant may have a synergistic effect with BMP15 in hereditary OIT or act as a modifier gene in OIT development.

[This corrects the article DOI: 10.3389/fonc.2024.1461772.].

ObjectiveDevelop a predicting model that can help stratify patients with epithelial ovarian cancer (EOC) before platinum-based chemotherapy.Methods148 patients with pathologically confirmed EOC and with a minimum 5-year follow-up were retrospectively enrolled. Patients were classified into platinum-sensitive and platinum-resistant groups according to treatment responses. The correlation between clinical factors and drug sensitivity was evaluated using statistical tests. Approximately 700,000 single-nucleotide polymorphism (SNP) sites were assessed for association with drug sensitivity via the Genome-wide Association Study (GWAS). LASSO regression and manual selection were employed to reduce the number of variables. A predicting model based on optimized variables was constructed. The predictive ability of the model was assessed using the Kaplan-Meier curve.ResultsNo statistically significant association was found between clinical factors and drug sensitivity. Sixteen SNPs were preserved after the optimization. A predicting model for drug sensitivity was constructed based on those sixteen SNPs. Coefficients of the synergistic effect for each SNP were determined, and an algorithm of the Drug Sensitivity Index (DSI) was built. The DSI score can successfully distinguish the drug-sensitive or drug-resistant patients with sensitivity, specificity, positive predictive value, and accuracy of 94.7%, 83.3%, 90.8%, and 90.5%, respectively. In both the training set and validating samples, the Kaplan-Meier curve showed that the median PFS and mean OS were significantly differentiated between the predicted sensitive and resistant patients (p-value<0.001).ConclusionsA mathematical model incorporating genotype information could help predict the drug sensitivity of platinum-based chemotherapy before the treatment in EOC patients. A personal chemotherapy could be achieved based on the model.

T-cell immunoglobulin and mucin domain-containing molecule 3 (TIM-3) has been reported to be overexpressed and associated with poor prognosis in solid tumors. However, its features and prognostic value in epithelial ovarian cancer (EOC) remain undetermined. In this study, we aimed to characterize TIM-3 expression and its prognostic significance in patients with EOC. A total of 134 EOC patients and 20 healthy controls from North China were included. TIM-3 mRNA and protein expression in EOC tumor tissues and benign ovarian tissues were detected by real-time quantitative PCR and immunohistochemistry. The distribution of TIM-3 protein in different regions of EOC tissue (tumor cells and the tumor microenvironment) were evaluated by multicolor immunofluorescence. Associations between their expression and clinicopathological parameters as well as survival analyses were performed. The results showed that high expression levels of TIM-3 mRNA were significantly associated with shorter progression-free survival (PFS; P < .001, hazard ratio [HR] = 1.57, 95% confidence interval [CI] = 1.29-1.91) and overall survival (OS; P = .013, HR = 1.31, 95% CI = 1.06-1.63) durations in EOC patients. High TIM-3 expression levels in tumor cells had shorter PFS (HR = 1.62, 95% CI = 1.09-2.46, P = .018) and OS (HR = 1.81, 95% CI = 1.19-2.75, P = .006) compared with those low TIM-3 expression levels. Similarly, TIM-3 in the tumor microenvironment was also an independent factor that affected the clinical outcome of EOC patients (PFS: HR = 1.99, 95% CI = 1.29-3.08, P = .002; OS: HR = 2.13, 95% CI = 1.37-.30, P = .001). These findings indicated that IM-3 may be a potential biomarker for predicting prognosis and immunotherapy efficacy in patients with EOC, exerting different roles on tumor cells and tumor microenvironment.

This study aimed to investigate the expression levels of CD8+ and CD39+CD8+ T cells in both intratumoral (CK+) and stromal (CK-) regions, in conjunction with clinical parameters, to assess their potential impact on chemotherapy response and prognosis in epithelial ovarian cancer (EOC) patients. Formalin-fixed, paraffin-embedded (FFPE) surgical specimens from 129 patients with EOC were used to construct tissue microarrays (TMAs) for assessing the expression of CD8+ and CD39+CD8+ tumor-infiltrating lymphocytes (TILs). Cytokeratin (CK) immunolabeling was employed to distinguish epithelial tumor regions (CK+) from stromal regions (CK-) in EOC tissues. Independent prognostic factors were identified using univariate and multivariate Cox regression analyses, and these variables were incorporated into nomogram models to predict overall survival (OS). Patients in the platinum-sensitive group exhibited significantly higher expression levels of stromal CD8+ cells and CD39+CD8+ T cells, which were strongly correlated with platinum sensitivity compared with the platinum-resistant group (p < 0.0001 and p = 0.0004, respectively). Multivariate Cox regression analysis in the training cohort indicated that elevated stromal levels of CD39+ T cells and CD39+CD8+ T cells were independently associated with improved OS (HR = 2.587, p = 0.033; HR = 3.090, p = 0.008, respectively). Nomograms were developed to visually predict OS by integrating these biomarkers with relevant clinical indicators identified in the Cox regression analyses. Calibration curves demonstrated excellent concordance between predicted and observed survival outcomes. Elevated stromal levels of CD39+CD8+ T cells represent a promising prognostic biomarker for predicting platinum sensitivity and favorable prognosis in patients with advanced EOC. These findings may provide valuable insights into the tumor microenvironment and its role in modulating therapeutic responses.

BACKGROUND:Emerging evidence suggests that aberrantly expressed microRNAs (miRNAs) participate in endometriosis pathogenesis. miR-1229-5p participates in the pathogenesis of several disease, but its precise role and mechanism in endometriosis is unclear. METHODS:Endometrial tissues were obtained from patients with endometriosis and healthy controls. RT-qPCR and western blotting were employed to detect the expression levels of genes and proteins, respectively. Transcriptome sequencing and luciferase reporter assay were utilized to identify the target of miR-1229-5p. CCK-8, transwell assay, wound healing assay and flow cytometry assay were performed to evaluate the functional roles of miR-1229-5p. Finally, the clinical significance of miR-1229-5p was furtherly analyzed. RESULTS:MiR-1229-5p was upregulated in ectopic endometrium of ovarian endometriosis patients (n = 60) compared to normal endometria of controls (n = 40), and its expression also served as an indicator for endometriosis severity. STMN1 was identified as the target of miR-1229-5p by luciferase experiments, and its expression was significantly downregulated in ectopic endometrium. Functionally, miR-1229-5p overexpression promoted migration, invasion, and inhibited apoptosis of ESCs and Ishikawa cells. Meanwhile, upregulation of miR-1229-5p also facilitated the protein expression of Bcl-2, MMP2, MMP9, N-cadherin, and ZEB1, and repressed the protein levels of Bax and E-cadherin. Whereas downregulation of miR-1229-5p exerted opposite effects. Importantly, STMN1 overexpression could partially reverse the effects of miR-1229-5p upregulation. Mechanistically, miR-1229-5p activates the p38 mitogen-activated protein kinase (p38 MAPK) signaling via targeting STMN1. CONCLUSION:The newly identified miR-1229-5p-STMN1-p38 MAPK axis illustrates the molecular mechanism of endometriosis progression and offers a potential therapeutic target for treating endometriosis.

Endometrial carcinoma (EC) represents the most prevalent malignancy of the female genital tract in the United States, with lymphovascular space invasion (LVSI) recognized as a critical prognostic factor that significantly influences disease outcomes. This review aims to elucidate the evolving understanding of LVSI in early-stage EC, highlighting its implications for stratification, quantification, and clinical management. A systematic review was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Comprehensive searches of the PubMed, Web of Science, and Embase/MEDLINE databases were performed for studies published from January 1, 1985, to November 16, 2024. Peer-reviewed articles that reported multivariable hazard ratios (HR) for LVSI in endometrial cancer were included, while meta-analyses, reviews, and case reports were excluded from analysis. A total of 6 studies involving 2,345 patients were included. The majority of the population was characterized by endometrioid histotype (85.7

Immune cells within tumor tissues play important roles in remodeling the tumor microenvironment, thus affecting tumor progression and the therapeutic response. The current study was designed to identify key markers of plasma cells and explore their role in high-grade serous ovarian cancer (HGSOC). We utilized single-cell sequencing data from the Gene Expression Omnibus (GEO) database to identify key immune cell types within HGSOC tissues and to extract related markers via the Seurat package. The effects of immune cell markers on prognosis were analyzed via univariate Cox regression, least absolute shrinkage and selection operator (LASSO) and gene set variation analysis (GSVA) of bulk sequencing data from The Cancer Genome Atlas (TCGA)-HGSOC cohort. Finally, the effects of key markers on HGSOC cells were evaluated via Cell Counting Kit-8 (CCK-8), Transwell, colony formation, wound healing, immunofluorescence and in vivo tumor growth assays. At the single-cell level, we detected a significant increase in the proportion of plasma cells in HGSOC samples compared to that in normal ovarian samples. Within HGSOC tissues, these plasma cells were found to interact with CD8 + T cells, fibroblasts and endothelial cells. In addition, patients in the high-plasma cell-related score group had better survival rates and higher epithelial‒mesenchymal transition (EMT), apoptosis and immune scores. Moreover, univariate Cox and LASSO regression analyses revealed that ubiquitin-conjugating enzyme E2 J1 (UBE2J1) is a prognostic marker in HGSOC. Further functional studies revealed that overexpression of UBE2J1 promoted cell proliferation, invasion, migration and colony formation, whereas UBE2J1 knockdown attenuated the abovementioned cellular behaviors. Additionally, UBE2J1 overexpression promoted EMT, as evidenced by alterations in the protein expression levels of N-cadherin, snail family transcriptional repressor 2 (Slug), Twist family BHLH transcription factor 1 (Twist 1) and E-cadherin. Moreover, we found that UBE2J1 silencing was able to inhibit the tumor growth in vivo. Overall, this study elucidated the role of plasma cells and revealed UBE2J1 as a novel oncogene in HGSOC, uncovering new mechanisms related to HGSOC tumorigenesis and promising therapeutic targets for HGSOC patients.

Ovarian cancer (OC) is a highly lethal gynecological cancer. Olaparib maintenance therapy was effective and well-tolerated in pivotal RCTs. However, nationwide real-world safety information is limited in China. This multicenter, prospective, observational drug intensive monitoring study monitored the safety of olaparib in a largest-to-date, real-world Chinese OC cohort. Eligible OC patients had received ≥ 1 dose of olaparib. Follow-up extended up to 30 days post-olaparib discontinuation or maximally for six months post-enrolment. Primary and secondary endpoints were adverse events (AEs) in all OC patients and in special populations (hepatically/renally impaired before olaparib treatment; aged > 65 years), respectively. By Jun 30, 2023, 799 patients from 33 sites were enrolled. By data cut-off (Dec 29, 2023), 796 patients treated with olaparib were analyzed. The median age was 55 years (range, 25–85). Of 796 patients, 490 (61.6

BackgroundCervical cancer (CC) is a leading cause of cancer-related death in women. The N-myc down-stream regulatory gene (NDRG) family has an unclear prognostic role in CC.MethodsWe analyzed NDRG mRNA and protein levels in CC using public databases. And NDRG1 expression was verified through immunohistochemistry in clinical samples. Additionally, we utilized other bioinformatics tools to analyze the correlations between NDRG and survival, as well as immune infiltration.ResultsNDRG1 was elevated, and NDRG2 was reduced in CC tissues. High NDRG1 and low NDRG2/3 correlated with poorer survival and were associated with reduced immune cell infiltration, particularly CD8+ T cells. Genetic alterations in NDRG1/2/3 were primarily amplifications, while DNA hypomethylation of NDRG1 in CC tissues, particularly at specific CpG sites, was associated with prognosis. PPI and enrichment analyses implicated NDRGs in metabolic processes, HIF-1 signaling, and immune regulation, underscoring their roles in CC progression and prognosis.ConclusionsNDRG1/2 present potential as new prognostic biomarkers, shedding light on therapeutic targets for CC.

BackgroundFerroptosis, a recently discovered iron-dependent cell death, is linked to various diseases but its role in endometriosis is still not fully understood.MethodsIn this study, we integrated microarray data of endometriosis from the GEO database and ferroptosis-related genes (FRGs) from the FerrDb database to further investigate the regulation of ferroptosis in endometriosis and its impact on the immune microenvironment. WGCNA identified ferroptosis-related modules, annotated by GO & KEGG. MNC algorithm pinpointed hub FRGs. Cytoscape construct a ceRNA network, and ROC curves evaluated diagnostic efficacy of hub FRGs. Consensus cluster analysis identified ferroptosis subclusters, and CIBERSORT assessed immune infiltration of these subclusters. Finally, RT-qPCR validated hub FRG expression in clinical tissues.ResultsWe identified two ferroptosis modules of endometriosis, and by enrichment analysis, they are closely linked with autophagy, mTOR, oxidative stress, and FOXO pathways. Furthermore, we identified 10 hub FRGs, and the ROC curve showed better predictive ability for diagnosing. RT-qPCR confirmed that the tissue expression of 10 hub FRGs was mostly consistent with the database results. Subsequently, we developed a ceRNA network based on 4 FRGs (BECN1, OSBPL9, TGFBR1, GSK3B). Next, we identified two ferroptosis subclusters of endometriosis and discovered that they are closely linked with endometriosis stage. Importantly, immune enrichment analysis illustrated that the expression levels of immune cells and immune checkpoint genes were significantly different in the two ferroptosis subclusters. Specifically, the ferroptosis subcluster with stage III-IV of endometriosis is more inclined to the immunosuppressive microenvironment.ConclusionsOur study showed that ferroptosis may jointly promote endometriosis progression by remodeling the immune microenvironment, offering new insights into pathogenesis and therapeutics.

5522 Background: Enlonstobart is a PD-1 inhibitor that has demonstrated durable anti-tumor activity and acceptable safety in patients with PD-L1 positive recurrent/metastatic cervical cancer in a multicenter, single-arm, open-label, phase II study. At primary cutoff date (May 27, 2023), the overall survival (OS) was not reached. Here, we report results from a pre-planned further follow-up (August 20, 2024). Methods: Eligible patients were ≥18 years old with PD-L1-positive (combined positive score ≥ 1) cervical cancer who had progression during or after or intolerance to the first-line platinum-based therapy. A total of 107 patients received enlonstobart 240 mg every two weeks for up to 24 months or until disease progression, intolerable toxicities, or other study discontinuation criteria were met. At the updated cutoff date, analyses of progression-free survival (PFS) and OS in the full analysis set (FAS), which consisted of all patients who had received at least one dose of enlonstobart treatment, and the per protocol set (PPS), which consisted of all patients in the FAS who had at least one available postbaseline tumor assessment were conducted. Results: At the cutoff date of August 20 2024, the median follow-up time was 15.84 months (range 0.4 ~ 35.6 months). In FAS, the median PFS was 3.06 (95 % CI 2.23–6.90) months. The median OS was 19.38 (95 % CI 14.95–25.40) months and the estimated OS rate was 68.14 % (95 %CI 58.20–76.19) at 12 months, 50.78 % (95 % CI 40.46–60.20) at 18 months, and 42.84 % (95 % CI 32.76–52.53) at 24 months. In PPS, the median PFS was 3.81 (95 % CI 2.63–7.49) months. The median OS was 21.26 (95 % CI 15.44–27.66) months and the estimated OS rate was 71.53 % (95 %CI 61.48–79.40) at 12 months, 53.32 % (95 % CI 42.64–62.87) at 18 months, and 44.98 % (95 % CI 34.50–54.89) at 24 months. Conclusions: Enlonstobart monotherapy showed a promising survival in patients with PD-L1 positive recurrent/metastatic cervical cancer, whose disease experienced progression after first-line platinum-based therapy. Clinical trial information: NCT04886700 .

The importance of epithelial‒mesenchymal transition (EMT) in tumour invasion and metastasis in high-grade serous ovarian cancer (HGSOC) has been highlighted in numerous studies, but genetic biomarkers for predicting EMT in HGSOC are still lacking. The role of EMT hallmarks and the relationship between EMT and the tumour microenvironment in HGSOC were examined based on transcriptomic data from 366 HGSOC patients in the TCGA dataset via the GSVA algorithm, the ESTIMATE method and Pearson correlation analyses. Furthermore, machine learning was applied to determine key EMT signatures and classify EMT subtypes. Moreover, the role of the key EMT signature ADAMTS2 in the behaviour and EMT process of HGSOC cells was detected via western blot, CCK8, transwell, wound healing and immunofluorescence assays. The expression of EMT hallmarks (EMT score) was significantly associated with the progression, immune microenvironment and prognosis of HGSOC patients. Different machine learning algorithms identified MMP2, ADAMTS2, FN1, THBS2, C3ORF80, FAP and POSTN as key EMT-related signatures in HGSOC. Finally, qPCR, western blotting and IHC staining consistently revealed elevated expression of ADAMTS2 in five ovarian cancer tissues from HGSOC patients and five normal ovarian epithelial tissues from five uterine prolapse patients. Further in vitro experiments revealed that ADAMTS2 knockdown inhibited cell proliferation, migration, and invasion as well as the expression of TNF-α, IL-1β and EMT markers (E-cadherin, N-cadherin, SLUG, and TWIST1), whereas ADAMTS2 overexpression promoted the above cellular behaviours and increased the expression of TNF-α, IL-1β and EMT markers. Our study presents a new classifier to predict EMT and the immune microenvironment in HGSOC and identifies ADAMTS2 as a novel regulator of the EMT process. These findings might promote the development of EMT-related immunotherapeutic strategies for HGSOC patients.

Growing evidence indicates that aberrant methylation is pivotal in the development and progression of endometriosis (EMs). This study explores the relationship between abnormal methylation of the ENPP3 promoter and the pathogenesis of ovarian EMs, focusing on its regulatory effect on ENPP3 expression. We analyzed the methylation levels of ENPP3 in ectopic endometrial tissues from ovarian EMs patients and in normal endometrial tissues from women without EMs. The expression and distribution of ENPP3 were evaluated using RT-qPCR and immunohistochemistry. Transwell assays were conducted to examine the impact of ENPP3 overexpression on the migratory and invasive capabilities of endometrial stromal cells. Our results demonstrated significantly reduced methylation levels at the CpG sites of the ENPP3 promoter region in ectopic endometrial tissues compared to normal endometrial tissues. RT-qPCR findings revealed a marked increase in ENPP3 expression in ovarian EMs tissues relative to endometrial tissues from patients without EMs, and this upregulation was negatively correlated with the methylation levels of the ENPP3 promoter region. Immunohistochemical analyses confirmed elevated ENPP3 expression in the glandular epithelial cells and stroma of ovarian EMs tissues. Furthermore, in vitro experiments showed that overexpressed ENPP3 notably intensified the invasion and migration of endometrial stromal cells. Transcriptome sequencing and functional analyses indicated that the increased ENPP3 expression activated the AKT/mTOR/4EBP1 signaling pathway. In summary, the study suggests that hypomethylation in the ENPP3 promoter region may contribute to the initiation and advancement of ovarian EMs by activating the AKT/mTOR/4EBP1 pathway, supporting the theory that EMs might be an epigenetically regulated disorder.

OBJECTIVE:The purpose of this experiment is to explore the role of long intergenic noncoding RNA 261 (LINC00261) gene in the chemoresistance and clinical prognosis of epithelial ovarian cancer (EOC). METHODS:We used matrix-assisted laser desorption ionization time-of-flight (MALDI-TOF) mass spectrometry to detect the methylation levels of the LINC00261 promoter region in EOC patient specimens. The expression levels of LINC00261, miR-545-3p, and MT1M in EOC patients were evaluated by quantitative real-time reverse transcriptase PCR (RT-qPCR). Spearman's correlation analysis was used for relevance analyses and clinical prognosis was counted by Kaplan-Meier analysis. Stable overexpressed LINC00261 SKOV3 cells were established to test the influence of LINC00261 on proliferation, platinum sensitivity, migration, and invasion. RESULTS:The promoter region methylation level of the LINC00261 was hypermethylated and LINC00261 was significantly downregulated in platinum-resistant EOC tissues. The methylation level of LINC00261was significantly negative correlated with its RNA expression in EOC. Moreover, hypermethylation and lower expression of LINC00261 in EOC patients were related to shorter progression-free survival (PFS) and overall survival (OS). Furthermore, Spearman's correlation analysis showed that the expression of miR-545-3p had a negative relevance with LINC00261. According to the website prediction, MT1M might be the downstream target gene of LINC00261. Expression of MT1M was negatively correlated with miR-545-3p and positively with LINC00261 in EOC tissues. And lower MT1M mRNA expression was correlated with chemotherapy resistance and worse prognosis. In vitro, overexpression of LINC00261 could inhibit cisplatin resistance, proliferation, and suppression of migration and invasion in SKOV3 cells. CONCLUSIONS:This research indicates that the aberrant hypermethylation and low expression of LINC00261 were associated with platinum resistance and adverse outcomes in EOC patients.

OBJECTIVE:This multicenter study aimed to investigate the disparity in clinical features and prognosis among different histopathologic subtypes of endocervical adenocarcinoma (EA) based on the 2014 World Health Organization (WHO) classification. METHODS:We retrieved and analyzed data from the Chinese Four C Database between 2004 and 2018. 672EA patients with radical hysterectomies from 32 institutions were retrospectively reviewed. Clinicopathologic characteristics, five-year overall survival (OS), and disease-free survival (DFS) were compared based on histological subtypes. RESULTS:The 5-year DFS and OS rates for usual, endometrioid, mucinous, gastric, villoglandular, clear cell/serous/mesonephric EAs were as follows: 81.3 %, 89.1 %, 63.0 %, 35.6 %, 88.6 %, 79.9 %, respectively (P < 0.0001); 87.4 %, 96.6 %, 74.7 %, 34.0 %, 96.7 %, 86.3 %, respectively (P < 0.0001). Gastric- and mucinous-type exhibited a higher frequency of lymph node metastasis, deep stromal invasion, uterine corpus invasion, and recurrence than the usual -type (recurrence rate:50.00 % vs 29.90 % vs 15.50 %, P < 0.0001). Multivariate analysis revealed gastric-type was significantly associated with inferior DFS (HR,3.018; 95 % CI, 1.688-5.397; P < 0.0001) and OS(HR, 4.114; 95 % CI, 2.002-8.453; P < 0.0001). Furthermore, compared to the usual -type, mucinous-type demonstrated significantly worse DFS (HR, 1.773; 95 % CI,1.123-2.8; P = 0.014) and OS (HR, 2.168; 95 % CI,1.214-3.873; P = 0.009) whereas endometrioid-type was an identified as independent factor for better DFS (HR, 0.365; 95 % CI,0.143-0.928; P = 0.034). Villoglandular subtype displayed similar features and favorable prognosis as the usual type. CONCLUSIONS:Relevant clinical features and prognosis varied significantly among histological subtypes of EA, thus offering valuable guidance for the development of subtype-specific treatment strategies to optimize EA management.