PRKDC-Mediated NHEJ May Play a Crucial Role in Aneuploidy of Chromosome 8-Driven Progression of Ovarian Cancer.

High malignancy is a prominent characteristic of epithelial ovarian cancer (EOC), emphasizing the necessity for further elucidation of the potential mechanisms underlying cancer progression. Aneuploidy and copy number variation (CNV) partially contribute to the heightened malignancy observed in EOC; however, the precise features of aneuploidy and their underlying molecular patterns, as well as the relationship between CNV and aneuploidy in EOC, remain unclear. In this study, we employed single-cell sequencing data along with The Cancer Genome Atlas (TCGA) to investigate aneuploidy and CNV in EOC. The technique of fluorescence in situ hybridization (FISH) was employed using specific probes. The copy number variation within the genomic region of chromosome 8 (42754568-47889815) was assessed and utilized as a representative measure for the ploidy status of individual cells in chromosome 8. Differential expression analysis was performed between different subgroups based on chromosome 8 ploidy. Gene ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), protein-protein interaction (PPI), and hub-gene analyses were subsequently utilized to identify crucial genes involved. By classifying enriched tumor cells into distinct subtypes based on chromosome 8 ploidy combined with TCGA data integration, we identified key genes driving chromosome 8 aneuploidy in EOC, revealing that PRKDC gene involvement through the mediated non-homologous end-joining pathway may play a pivotal role in disease progression. Further validation through analysis of the GEO and TCGA database and survival assessment, considering both mRNA expression levels and CNV status of PRKDC, has confirmed its involvement in the progression of EOC. Further functional analysis revealed an upregulation of PRKDC in both ovarian EOC cells and tissues, with its expression showing a significant correlation with the extent of copy number variation (CNV) on chromosome 8. Taken together, CNV amplification and aneuploidy of chromosome 8 are important characteristics of EOC. PRKDC and the mediated NHEJ pathway may play a crucial role in driving aneuploidy on chromosome 8 during the progression of EOC.

Prognostic factors and the role of primary debulking in operable stage IVB ovarian cancer with supraclavicular lymph node metastasis: a retrospective study in Chinese patients.

BACKGROUND: Recent studies showed heterogeneity in stage IVB patients. However, few studies focused on the prognosis of supraclavicular metastatic ovarian cancer. This study aimed to explore the prognostic factors and the role of primary debulking in IVB ovarian cancer patients with supraclavicular lymph node metastasis. METHODS: We retrospectively analyzed patients newly diagnosed as primary epithelial ovarian cancer with supraclavicular lymph node metastasis from January 2015 to July 2020. Supraclavicular lymph node metastasis was defined as either the pathological diagnosis by supraclavicular lymph node biopsy, or the radiological diagnosis by positron emission tomography-computed tomography (PET-CT). RESULTS: In 51 patients, 37 was diagnosed with metastatic supraclavicular lymph nodes by histology, 46 by PET-CT, and 32 by both methods. Forty-four (86.3%) with simultaneous metastatic paraaortic lymph nodes (PALNs) by imaging before surgery or neoadjuvant chemotherapy were defined as "continuous-metastasis type", while the other 7 (13.7%) defined as "skip-metastasis type". Nineteen patients were confirmed with metastatic PALNs by histology. Thirty-four patients were investigated for BRCA mutation, 17 had germline or somatic BRCA1/2 mutations (g/sBRCAm). With a median follow-up of 30.0 months (6.3-63.4 m), 16 patients (31.4%) died. The median PFS and OS of the cohort were 17.3 and 48.9 months. Survival analysis showed that "continuous-metastasis type" had longer OS and PFS than "skip-metastasis type" (OS: 50.0/26.6 months, PFS: 18.5/7.2months, p=0.005/0.002). BRCA mutation carriers also had longer OS and PFS than noncarriers (OS: 57.4 /38.5 m, p=0.031; PFS: 23.6/15.2m, p=0.005). Multivariate analysis revealed only metastatic PALNs was independent prognostic factor for OS (p=0.040). Among "continuous-metastasis type" patients, 22 (50.0%) achieved R0 abdominopelvic debulking, who had significantly longer OS (55.3/42.3 months, p =0.034) than those with residual abdominopelvic tumors. CONCLUSIONS: In stage IVB ovarian cancer patients with supraclavicular lymph nodes metastasis, those defined as "continuous-metastasis type" with positive PALNs had better prognosis. For them, optimal abdominopelvic debulking had prognostic benefit, although metastatic supraclavicular lymph nodes were not resected. Higher BRCA mutation rate than the general population of ovarian cancer patients was observed in patients with IVB supraclavicular lymph node metastasis, leading to better survival as expected.

Characterization of innate lymphoid cell subsets infiltrating melanoma and epithelial ovarian tumors.

The innate lymphoid cell (ILC) family is composed of heterogeneous innate effector and helper immune cells that preferentially reside in tissues where they promote tissue homeostasis. In cancer, they have been implicated in driving both pro- and anti-tumor responses. This apparent dichotomy highlights the need to better understand differences in the ILC composition and phenotype within different tumor types that could drive seemingly opposite anti-tumor responses. Here, we characterized the frequency and phenotype of various ILC subsets in melanoma metastases and primary epithelial ovarian tumors. We observed high PD-1 expression on ILC subsets isolated from epithelial ovarian tumor samples, while ILC populations in melanoma samples express higher levels of LAG-3. In addition, we found that the frequency of cytotoxic ILCs and NKp46+ILC3 in tumors positively correlates with monocytic cells and conventional type 2 dendritic cells, revealing potentially new interconnected immune cell subsets in the tumor microenvironment. Consequently, these observations may have direct relevance to tumor microenvironment composition and how ILC subset may influence anti-tumor immunity.

IL-6 regulates epithelial ovarian cancer EMT, invasion, and metastasis by modulating Let-7c and miR-200c through the STAT3/HIF-1α pathway.

Interleukin-6 (IL-6) and hypoxia-inducible factor-1α (HIF-1α) play important roles in epithelial-mesenchymal transformation (EMT) and tumor development. Previous studies have demonstrated that IL-6 promotes EMT, invasion, and metastasis in epithelial ovarian cancer (EOC) cells by activating the STAT3/HIF-1α pathway. MicroRNA (miRNA) is non-coding small RNAs that also play an important role in tumor development. Notably, Let-7 and miR-200 families are prominently altered in EOC. However, whether IL-6 regulates the expression of Let-7 and miR-200 families through the STAT3/HIF-1α signaling to induce EMT in EOC remains poorly understood. In this study, we conducted in vitro and in vivo investigations using two EOC cell lines, SKOV3, and OVCAR3 cells. Our findings demonstrate that IL-6 down-regulates the mRNA levels of Let-7c and miR-200c while up-regulating their target genes HMGA2 and ZEB1 through the STAT3/HIF-1α signaling in EOC cells and in vivo. Additionally, to explore the regulatory role of HIF-1α on miRNAs, both exogenous HIF blockers YC-1 and endogenous high expression or inhibition of HIF-1α can be utilized. Both approaches can confirm that the downstream molecule HIF-1α inhibits the expression and function of Let-7c and miR-200c. Further mechanistic research revealed that the overexpression of Let-7c or miR-200c can reverse the malignant evolution of EOC cells induced by IL-6, including EMT, invasion, and metastasis. Consequently, our results suggest that IL-6 regulates the expression of Let-7c and miR-200c through the STAT3/HIF-1α pathway, thereby promoting EMT, invasion, and metastasis in EOC cells.

The Clinicopathological Significance of the Cyclin D1/E1-Cyclin-Dependent Kinase (CDK2/4/6)-Retinoblastoma (RB1/pRB1) Pathway in Epithelial Ovarian Cancers.

Cyclin-dependent kinases (CDK2, CDK4, CDK6), cyclin D1, cyclin E1 and phosphorylated retinoblastoma (pRB1) are key regulators of the G1/S cell cycle checkpoint and may influence platinum response in ovarian cancers. CDK2/4/6 inhibitors are emerging targets in ovarian cancer therapeutics. In the current study, we evaluated the prognostic and predictive significance of the CDK2/4/6-cyclin D1/E1-pRB1 axis in clinical ovarian cancers (OC). The CDK2/4/6, cyclin D1/E1 and RB1/pRB1 protein expression were investigated in 300 ovarian cancers and correlated with clinicopathological parameters and patient outcomes. CDK2/4/6, cyclin D1/E1 and RB1 mRNA expression were evaluated in the publicly available ovarian TCGA dataset. We observed nuclear and cytoplasmic staining for CDK2/4/6, cyclins D1/E1 and RB1/pRB1 in OCs with varying percentages. Increased nuclear CDK2 and nuclear cyclin E1 expression was linked with poor progression-free survival (PFS) and a shorter overall survival (OS). Nuclear CDK6 was associated with poor OS. The cytoplasmic expression of CDK4, cyclin D1 and cyclin E1 also has predictive and/or prognostic significance in OCs. In the multivariate analysis, nuclear cyclin E1 was an independent predictor of poor PFS. Tumours with high nuclear cyclin E1/high nuclear CDK2 have a worse PFS and OS. Detailed bioinformatics in the TCGA cohort showed a positive correlation between cyclin E1 and CDK2. We also showed that cyclin-E1-overexpressing tumours are enriched for genes involved in insulin signalling and release. Our data not only identified the prognostic/predictive significance of these key cell cycle regulators but also demonstrate the importance of sub-cellular localisation. CDK2 targeting in cyclin-E1-amplified OCs could be a rational approach.

Diagnosing and staging epithelial ovarian cancer by serum glycoproteomic profiling.

BACKGROUND: There is a need for diagnostic tests for screening, triaging and staging of epithelial ovarian cancer (EOC). Glycoproteomics of blood samples has shown promise for biomarker discovery. METHODS: We applied glycoproteomics to serum of people with EOC or benign pelvic masses and healthy controls. A total of 653 analytes were quantified and assessed in multivariable models, which were tested in an independent cohort. Additionally, we analyzed glycosylation patterns in serum markers and in tissues. RESULTS: We identified a biomarker panel that distinguished benign lesions from EOC with sensitivity and specificity of 83.5% and 90.1% in the training set, and of 86.7 and 86.7% in the test set, respectively. ROC analysis demonstrated strong performance across a range of cutoffs. Fucosylated multi-antennary glycopeptide markers were higher in late-stage than in early-stage EOC. A comparable pattern was found in late-stage EOC tissues. CONCLUSIONS: Blood glycopeptide biomarkers have the potential to distinguish benign from malignant pelvic masses, and early- from late-stage EOC. Glycosylation of circulating and tumor tissue proteins may be related. This study supports the hypothesis that blood glycoproteomic profiling can be used for EOC diagnosis and staging and it warrants further clinical evaluation.

Outcomes after fertility-sparing surgery of early-stage ovarian cancer: A nationwide population-based study.

BACKGROUND: Fertility-sparing surgery (FSS) is an alternative choice of young patients who have not completed their family planning and still have fertility needs. The aims of this study were to compare the outcomes of early-stage epithelial ovarian cancer (EOC) patients undergoing FSS and radical comprehensive staging surgery (RCS), and the suitability of FSS. METHODS: A total of 1297 patients aged between 20 and 44 years with newly diagnosed early-stage EOC were recruited from the Taiwan Cancer Registry database between 2009 and 2017. Site-specific surgery codes were used to distinguish patients in FSS group or RCS group. Cancer-specific survival (CSS) was evaluated using Kaplan-Meier method with log-rank test and Cox regression model. RESULTS: There were 401 and 896 patients in FSS and RCS group. Patients in FSS group were with younger age and mostly had Stage I disease. In contrast, patients in RCS group were older. There were more Stage II, high-grade (Grade 3) disease, and adjuvant chemotherapy in RCS group. Stage and tumor grade were two independent factors correlating with CSS and the type of surgery showed no effect on CSS (HR: 1.09, 95% CI: 0.66-1.77, p = 0.73) in multivariable analysis. In multivariable analysis, the clear cell carcinoma group who underwent FSS demonstrated better CSS compared to those in the RCS group (HR: 0.28, 95% CI: 0.06-0.82, p = 0.04). A total of 17 women who underwent FSS developed second malignancies of the uterine corpus or contralateral ovary. CONCLUSION: FSS can be a safe alternative procedure in selected young patients of Stage I EOC who have fertility desire. Endometrial biopsy before or during FSS and regular surveillance to detect recurrence are mandatory for ovarian cancer patients undergoing FSS.

Spotlight on New Hallmarks of Drug-Resistance towards Personalized Care for Epithelial Ovarian Cancer.

Epithelial ovarian cancer (EOC) is the deadliest gynecological malignancy worldwide. Despite the latest advances, a major clinical issue in EOC is the disappointing prognosis related to chemoresistance in almost one-third of cases. Drug resistance relies on heterogeneous cancer stem cells (CSCs), endowed with tumor-initiating potential, leading to relapse. No biomarkers of chemoresistance have been validated yet. Recently, major signaling pathways, micro ribonucleic acids (miRNAs), and circulating tumor cells (CTCs) have been advocated as putative biomarkers and potential therapeutic targets for drug resistance. However, further investigation is mandatory before their routine implementation. In accordance with the increasing rate of therapeutic efforts in EOC, the need for biomarker-driven personalized therapies is growing. This review aims to discuss the emerging hallmarks of drug resistance with an in-depth insight into the underlying molecular mechanisms lacking so far. Finally, a glimpse of novel therapeutic avenues and future challenges will be provided.

Application of interpretable machine learning algorithms to predict distant metastasis in ovarian clear cell carcinoma.

BACKGROUND: Ovarian clear cell carcinoma (OCCC) represents a subtype of ovarian epithelial carcinoma (OEC) known for its limited responsiveness to chemotherapy, and the onset of distant metastasis significantly impacts patient prognoses. This study aimed to identify potential risk factors contributing to the occurrence of distant metastasis in OCCC. METHODS: Utilizing the Surveillance, Epidemiology, and End Results (SEER) database, we identified patients diagnosed with OCCC between 2004 and 2015. The most influential factors were selected through the application of Gaussian Naive Bayes (GNB) and Adaboost machine learning algorithms, employing a Venn test for further refinement. Subsequently, six machine learning (ML) techniques, namely XGBoost, LightGBM, Random Forest (RF), Adaptive Boosting (Adaboost), Support Vector Machine (SVM), and Multilayer Perceptron (MLP), were employed to construct predictive models for distant metastasis. Shapley Additive Interpretation (SHAP) analysis facilitated a visual interpretation for individual patient. Model validity was assessed using accuracy, sensitivity, specificity, positive predictive value, negative predictive value, F1 score, and the area under the receiver operating characteristic curve (AUC). RESULTS: In the realm of predicting distant metastasis, the Random Forest (RF) model outperformed the other five machine learning algorithms. The RF model demonstrated accuracy, sensitivity, specificity, positive predictive value, negative predictive value, F1 score, and AUC (95% CI) values of 0.792 (0.762-0.823), 0.904 (0.835-0.973), 0.759 (0.731-0.787), 0.221 (0.186-0.256), 0.974 (0.967-0.982), 0.353 (0.306-0.399), and 0.834 (0.696-0.967), respectively, surpassing the performance of other models. Additionally, the calibration curve's Brier Score (95%) for the RF model reached the minimum value of 0.06256 (0.05753-0.06759). SHAP analysis provided independent explanations, reaffirming the critical clinical factors associated with the risk of metastasis in OCCC patients. CONCLUSIONS: This study successfully established a precise predictive model for OCCC patient metastasis using machine learning techniques, offering valuable support to clinicians in making informed clinical decisions.

A randomized controlled trial to compare short-term outcomes following infragastric and infracolic omentectomy at the time of primary debulking surgery for epithelial ovarian cancer with normal-appearing omentum.

BACKGROUND: Omentectomy is an important procedure in surgery for epithelial ovarian cancer, but the scope of omentectomy is not recommended in the guidelines. This study was performed to evaluate the benefits and risks of infragastric omentectomy in patients with epithelial ovarian cancer. METHODS: This trial is a single center prospective study. Primary epithelial ovarian cancer patients with normal-appearing omentum were randomly assigned to either the control or experimental group and underwent infracolic or infragastric omentectomy, respectively. The primary endpoint was progression-free survival. This trial is registered on Chinese clinical trial registry site (ChiCTR1800018771). RESULTS: A total of 106 patients meeting the inclusion criteria for ovarian cancer were included during the study period. Of these, 53 patients underwent infracolic omentectomy, whereas 53 patients received infragastric omentectomy. Multivariate analysis revealed that infragastric omentectomy could improve the detection rate of omental metastases (OR: 6.519, P = 0.005). Infragastric omentectomy improved progression-free survival significantly for those cases with higher than stage IIB disease (HR: 0.456, P = 0.041). Based on the short-term results, infragastric omentectomy did not cause more perioperative complications. CONCLUSIONS: Compared with infracolic omentectomy, infragrastric omentectomy may be a more appropriate surgical procedure for stage IIB-IIIC epithelial ovarian cancer patients with normal-appearing omentum.

Comprehensive DNA methylation profiling by MeDIP-NGS identifies potential genes and pathways for epithelial ovarian cancer.

Ovarian cancer, among all gynecologic malignancies, exhibits the highest incidence and mortality rate, primarily because it is often presents with non-specific or no symptoms during its early stages. For the advancement of Ovarian Cancer Diagnosis, it is crucial to identify the potential molecular signatures that could significantly differentiate between healthy and ovarian cancerous tissues and can be used further as a diagnostic biomarker for detecting ovarian cancer. In this study, we investigated the genome-wide methylation patterns in ovarian cancer patients using Methylated DNA Immunoprecipitation (MeDIP-Seq) followed by NGS. Identified differentially methylated regions (DMRs) were further validated by targeted bisulfite sequencing for CpG site-specific methylation profiles. Furthermore, expression validation of six genes by Quantitative Reverse Transcriptase-PCR was also performed. Out of total 120 differentially methylated genes (DMGs), 68 genes were hypermethylated, and 52 were hypomethylated in their promoter region. After analysis, we identified the top 6 hub genes, namely POLR3B, PLXND1, GIGYF2, STK4, BMP2 and CRKL. Interestingly we observed Non-CpG site methylation in the case of POLR3B and CRKL which was statistically significant in discriminating ovarian cancer samples from normal controls. The most significant pathways identified were focal adhesion, the MAPK signaling pathway, and the Ras signaling pathway. Expression analysis of hypermethylated genes was correlated with the downregulation of the genes. POLR3B and GIGYF2 turned out to be the novel genes associated with the carcinogenesis of EOC. Our study demonstrated that methylation profiling through MeDIP-sequencing has effectively identified six potential hub genes and pathways that might exacerbate our understanding of underlying molecular mechanisms of ovarian carcinogenesis.

Olaparib Addition to Maintenance Bevacizumab Therapy in Ovarian Carcinoma With BRCA-Like Genomic Aberrations.

Importance: Testing for homologous recombination deficiency is required for the optimal treatment of high-grade epithelial ovarian cancer. The search for accurate biomarkers is ongoing. Objective: To investigate whether progression-free survival (PFS) and overall survival (OS) of patients with high-grade epithelial ovarian cancer treated with maintenance olaparib or placebo differed between patients with a tumor BRCA-like genomic profile and patients without a tumor BRCA-like profile. Design, Setting, and Participants: This cohort study was a secondary analysis of the PAOLA-1 randomized clinical trial that compared olaparib plus bevacizumab with placebo plus bevacizumab as maintenance treatment in patients with advanced high-grade ovarian cancer after a good response to first-line platinum with taxane chemotherapy plus bevacizumab, irrespective of germline or tumor BRCA1/2 mutation status. All patients with available tumor DNA were included in the analysis. The current analysis tested for an interaction between BRCA-like status and olaparib treatment on survival outcomes. The original trial was conducted between July 2015 and September 2017; at the time of data extraction for analysis in March 2022, a median follow-up of 54.1 months (IQR, 28.5-62.2 months) and a total follow-up time of 21 711 months was available, with 336 PFS and 245 OS events. Exposures: Tumor homologous recombination deficiency was assessed using the BRCA-like copy number aberration profile classifier. Myriad MyChoice CDx was previously measured. The trial was randomized between the olaparib and bevacizumab and placebo plus bevacizumab groups. Main Outcomes and Measures: This secondary analysis assessed hazard ratios (HRs) of olaparib vs placebo among biomarker strata and tested for interaction between BRCA-like status and olaparib treatment on PFS and OS, using Cox proportional hazards regression. Results: A total of 469 patients (median age, 60 [range 26-80] years) were included in this study. The patient cohort consisted of women with International Federation of Gynaecology and Obstetrics stage III (76%) high-grade serous (95%) ovarian cancer who had no evaluable disease or complete remission at initial or interval debulking surgery (76%). Thirty-one percent of the tumor samples (n = 138) harbored a pathogenic BRCA mutation, and BRCA-like classification was performed for 442 patients. Patients with a BRCA-like tumor had a longer PFS after olaparib treatment than after placebo (36.4 vs 18.6 months; HR, 0.49; 95% CI, 0.37-0.65; P < .001). No association of olaparib with PFS was found in patients with a non-BRCA-like tumor (17.6 vs 16.6 months; HR, 1.02; 95% CI, 0.68-1.51; P = .93). The interaction was significant (P = .004), and HRs and P values (for interaction) were similar in the relevant subgroups, OS, and multivariable analyses. Conclusions and Relevance: In this secondary analysis of the PAOLA-1 randomized clinical trial, patients with a BRCA-like tumor, but not those with a non-BRCA-like tumor, had a significantly longer survival after olaparib plus bevacizumab treatment than placebo plus bevacizumab treatment. Thus, the BRCA1-like classifier could be used as a biomarker for olaparib plus bevacizumab as a maintenance treatment.

Ovarian serous carcinoma with stomach metastasis: a rare case report and literature review.

Ovarian cancer is a common tumor among women. It is often asymptomatic in the early stages, with most cases already at stage III to IVE at the time of diagnosis. Direct spread and lymphatic metastasis are the primary modes of metastasis, whereas hematogenous spread is rare. An initial diagnosis of ovarian cancer that has metastasized to the stomach is also uncommon. Therefore, clear treatment methods and prognostic data for such metastasis are lacking. In our hospital, we encountered a patient with an initial imaging diagnosis of a gastric tumor and a history of an ovarian tumor with endoscopic abdominal metastasis. Based on the characteristics of the case, the two tumors were considered to be the same. After chemotherapy, a partial response was observed in the stomach and pelvic lesions, suggesting the effectiveness of the treatment. Through three treatments of recurrence, gastroscopy confirmed the stomach to be a metastatic site. Therefore, determining the primary source of advanced tumors is crucial in guiding treatment decisions. Clinicians must approach this comprehensively, relying on thorough evaluation and personal experience.

A Stem-like Patient-Derived Ovarian Cancer Model of Platinum Resistance Reveals Dissociation of Stemness and Resistance.

To understand chemoresistance in the context of cancer stem cells (CSC), a cisplatin resistance model was developed using a high-grade serous ovarian cancer patient-derived, cisplatin-sensitive sample, PDX4. As a molecular subtype-specific stem-like cell line, PDX4 was selected for its representative features, including its histopathological and BRCA2 mutation status, and exposed to cisplatin in vitro. In the cisplatin-resistant cells, transcriptomics were carried out, and cell morphology, protein expression, and functional status were characterized. Additionally, potential signaling pathways involved in cisplatin resistance were explored. Our findings reveal the presence of distinct molecular signatures and phenotypic changes in cisplatin-resistant PDX4 compared to their sensitive counterparts. Surprisingly, we observed that chemoresistance was not inherently linked with increased stemness. In fact, although resistant cells expressed a combination of EMT and stemness markers, functional assays revealed that they were less proliferative, migratory, and clonogenic-features indicative of an underlying complex mechanism for cell survival. Furthermore, DNA damage tolerance and cellular stress management pathways were enriched. This novel, syngeneic model provides a valuable platform for investigating the underlying mechanisms of cisplatin resistance in a clinically relevant context, contributing to the development of targeted therapies tailored to combat resistance in stem-like ovarian cancer.

The evaluation of miR-1181 and miR-4314 as serum microRNA biomarkers for epithelial ovarian cancer diagnosis and prognosis.

AIM: Epithelial ovarian cancer (EOC) is the most ominous tumor of gynecological cancers due to its poor early detection rate and unfavorable prognosis. To date, there is no reliable screening method for the diagnosis of ovarian cancer at an early stage. MiRNAs are small non-coding RNA molecules, and their main function is to regulate gene expression. The present study compared the serum miR-1181 and miR-4314 levels in patients with EOC and healthy controls to measure the diagnostic and prognostic value as candidate biomarkers. MATERIALS AND METHODS: We collected serum samples from a total of 135 participants (69 patients with EOC and 66 healthy controls). Relative expressions of miR-1181 and miR-4314 were measured by quantitative real-time polymerase chain reaction assay (qPCR). RESULTS: The present study revealed that both serum miR-1181 and miR-4314 levels in patients with EOC were significantly increased compared to healthy controls for each marker. In addition, there was a significant relationship between miR-1181 and miR-4314 overexpressions and the stage and prognosis of the disease. Finally, patients with high expression levels of miR-1181 and miR-4314 had significantly shorter survival rates than those with low expression levels. CONCLUSION: The current study proposed that serum miR-1181 and miR-4314 could discriminate the EOC patients from healthy controls. In addition, both miR-1181 and miR-4314 may be predictive biomarkers for ovarian cancer prognosis. Further studies are needed to confirm the findings of the present study.

Effects of silencing hsa_circ_0015326 on proliferation, migration, invasion, and apoptosis of epithelial ovarian cancer cells.

Although the treatment of ovarian cancer has made great progress, there are still many patients who are not timely detected and given targeted therapy due to unknown pathogenesis. Recent studies have found that hsa_circ_0015326 is upregulated in ovarian cancer and is involved in the proliferation, invasion, and migration of ovarian cancer cells. However, whether hsa_circ_0015326 can be used as a new target of ovarian cancer needs further investigation. Therefore, the effect of hsa_circ_0015326 on epithelial ovarian cancer was investigated in this study. At first, si-hsa_circ_0015326 lentivirus was transfected into epithelial ovarian cancer cells. Then real-time fluorescence quantitative PCR (qRT-PCR) was used to detect hsa_circ_0015326 level. The proliferation of ovarian cancer cells was detected by CCK-8 assay. The horizontal and vertical migration abilities of the cells were detected by wound-healing assay and Transwell assay, respectively. Transwell assay was also used to determine the invasion rate. As for the apoptosis rate, it was assessed by flow cytometry. As a result, the expression level of hsa_circ_0015326 in A2780 and SKOV3 was found to be higher than that in IOSE-80. However, after transfecting si-hsa_circ_0015326 and si-NC into the cells, the proliferation, migration, and invasion abilities of A2780 and SKOV3 cells in the si-hsa_circ_0015326 group were significantly reduced in comparison to those in the si-NC and mock groups, while their apoptosis rates were elevated. Collectively, silencing hsa_circ_0015326 bears the capability of inhibiting the proliferation, migration, and invasion of ovarian cancer cells while increasing apoptosis rate. It can be concluded that hsa_circ_0015326 promotes the malignant biological activities of epithelial ovarian cancer cells.

Targeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade.

Aberrant glycosylation is a crucial strategy employed by cancer cells to evade cellular immunity. However, it's unclear whether homologous recombination (HR) status-dependent glycosylation can be therapeutically explored. Here, we show that the inhibition of branched N-glycans sensitizes HR-proficient, but not HR-deficient, epithelial ovarian cancers (EOCs) to immune checkpoint blockade (ICB). In contrast to fucosylation whose inhibition sensitizes EOCs to anti-PD-L1 immunotherapy regardless of HR-status, we observe an enrichment of branched N-glycans on HR-proficient compared to HR-deficient EOCs. Mechanistically, BRCA1/2 transcriptionally promotes the expression of MGAT5, the enzyme responsible for catalyzing branched N-glycans. The branched N-glycans on HR-proficient tumors augment their resistance to anti-PD-L1 by enhancing its binding with PD-1 on CD8+ T cells. In orthotopic, syngeneic EOC models in female mice, inhibiting branched N-glycans using 2-Deoxy-D-glucose sensitizes HR-proficient, but not HR-deficient EOCs, to anti-PD-L1. These findings indicate branched N-glycans as promising therapeutic targets whose inhibition sensitizes HR-proficient EOCs to ICB by overcoming immune evasion.

Stearoyl-CoA desaturase 1 inhibition induces ER stress-mediated apoptosis in ovarian cancer cells.

Ovarian cancer is a leading cause of death among gynecologic tumors, often detected at advanced stages. Metabolic reprogramming and increased lipid biosynthesis are key factors driving cancer cell growth. Stearoyl-CoA desaturase 1 (SCD1) is a crucial enzyme involved in de novo lipid synthesis, producing mono-unsaturated fatty acids (MUFAs). Here, we aimed to investigate the expression and significance of SCD1 in epithelial ovarian cancer (EOC). Comparative analysis of normal ovarian surface epithelial (NOSE) tissues and cell lines revealed elevated SCD1 expression in EOC tissues and cells. Inhibition of SCD1 significantly reduced the proliferation of EOC cells and patient-derived organoids and induced apoptotic cell death. Interestingly, SCD1 inhibition did not affect the viability of non-cancer cells, indicating selective cytotoxicity against EOC cells. SCD1 inhibition on EOC cells induced endoplasmic reticulum (ER) stress by activating the unfolded protein response (UPR) sensors and resulted in apoptosis. The addition of exogenous oleic acid, a product of SCD1, rescued EOC cells from ER stress-mediated apoptosis induced by SCD1 inhibition, underscoring the importance of lipid desaturation for cancer cell survival. Taken together, our findings suggest that the inhibition of SCD1 is a promising biomarker as well as a novel therapeutic target for ovarian cancer by regulating ER stress and inducing cancer cell apoptosis.

Genetically identification of endometriosis and cancers risk in women through a two-sample Mendelian randomization study.

Endometriosis is a prevalent and chronic inflammatory gynecologic disorder affecting approximately 6-10% of women globally, and has been associated with an increased risk of cancer. Nevertheless, previous studies have been hindered by methodological limitations that compromise the validity and robustness of their findings. In this study we conducted a comprehensive two-sample Mendelian randomization analysis to explore the genetically driven causal relationship between endometriosis and the risk of cancer. We conducted the analysis via the inverse variance weighted method, MR Egger method, and weighted median method utilizing publicly available genome-wide association study summary statistics. Furthermore, we implemented additional sensitivity analyses to assess the robustness and validity of the causal associations identified. We found strong evidence of a significant causal effect of endometriosis on a higher risk of ovarian cancer via inverse-variance weighted method (OR = 1.19, 95% CI 1.11-1.29, p < 0.0001), MR-Egger regression, and weighted median methodologies. Remarkably, our findings revealed a significant association between endometriosis and an increased risk of clear cell ovarian cancer (OR = 2.04, 95% CI 1.66-2.51, p < 0.0001) and endometrioid ovarian cancer (OR = 1.45, 95% CI 1.27-1.65, p < 0.0001). No association between endometriosis and other types of cancer was observed. We uncovered a causal relationship between endometriosis and an elevated risk of ovarian cancer, particularly clear cell ovarian cancer and endometrioid ovarian cancer. No significant associations between endometriosis and other types of cancer could be identified.

Profiling of Tumour-Infiltrating Lymphocytes and Tumour-Associated Macrophages in Ovarian Epithelial Cancer-Relation to Tumour Characteristics and Impact on Prognosis.

Early evidence suggests a strong impact of tumour-infiltrating lymphocytes (TILs) on both the prognosis and clinical behaviour of ovarian cancer. Proven associations, however, have not yet translated to successful immunotherapies and further work in the field is urgently needed. We aimed to analyse the tumour microenvironment of a well-characterised cohort of ovarian cancer samples. Tumour markers were selected owing to their comparative underrepresentation in the current literature. Paraffin-embedded, formalin-fixed tumour tissue blocks of 138 patients representative of the population and including early stage disease were identified, stained for CD3, CD20, CD68 and CD163 and analysed for both the stromal and intertumoral components. Data were statistically analysed in relation to clinical details, histological subtype, borderline vs. malignant status, survival and management received. Mean stromal CD3, total CD3 count, mean stromal CD20 and total CD20 count all correlated negatively with survival. Malignant ovarian tumours consistently demonstrated significantly higher infiltration of all analysed immune cells than borderline tumours. Assessment of the stromal compartment produced a considerably higher proportion of significant results when compared to the intra-tumoural infiltrates. Customary assessment of solely intra-tumoural cells in advanced stage disease patients undergoing primary debulking surgery should be challenged, with recommendations for future scoring systems provided.