Development Of Ovarian Cancer Research Articles

Abstract 4258: Racial and ethnic differences in the mutational landscape of low-grade serous ovarian cancer

Abstract Objective To characterize the mutational landscape of low grade serous ovarian cancer (LGSOC) with racial/ethnic stratification. Methods The AACR Project GENIE database version 12.0 was queried via cBioPortal (http://genie.cbioportal.org) for low-grade serous ovarian cancer (LGSOC) samples. This is a publicly available, de-identified, multi-institutional database of next-generation sequencing genomic profiling results for tumor samples. Mutation frequencies for 9 homologous recombination deficiency (HRD) genes, 4 MAP-Kinase (MAP-K) pathway genes and 6 mismatch-repair (MMR) deficiency genes were reported and compared between racial/ethnic groups using chi-squared or Fischer’s exact tests. The threshold used for statistical significance was a two-sided alpha of 0.05. Results Among 317 tumor samples of LGSOC, there were high rates of MAP-K pathway gene mutations but low rates of HRD, MMR and TP53 gene mutations (Table 1). Non-Hispanic Black patients had significantly higher rates of KRAS mutations compared to non-Hispanic White patients (6/7, 86% vs 48/178, 27%, p<0.01). There was no difference in KRAS mutation frequency among Asian (6/17, 35%), Hispanic (7/24, 29%) and Native American (2/2, 100%) patients when compared to non-Hispanic White patients. BRAF mutations were less common compared to KRAS mutations (32/317, 10%), with no racial/ethnic differences in mutation frequency. Conclusion High rates of MAP-K pathway mutations in LGSOC support development and trials of drugs targeting this pathway, such as MEK protein inhibitors. Furthermore, prior literature has demonstrated the prognostic advantage of KRAS and BRAF mutations in LGSOC as well as the association of KRAS mutations with progression of serous borderline tumors to LGSOC. These racial/ethnic differences in frequencies of these mutations are thus hypothesis generating for clinical research to evaluate the impact of race/ethnicity on the development and prognosis of this rare ovarian cancer. Mutation frequencies of HR, MAP-kinase, MMR and TP53 genes in low-grade serous ovarian cancer Gene No. of samples with ≥1 mutation No. of samples profiled for mutation Mutation frequency BRCA1 3 287 1.05 BRCA2 7 287 2.44 BRIP1 5 271 1.85 CHEK2 2 278 0.72 BARD1 2 239 0.84 RAD51B - - - RAD51C - - - RAD51D 2 246 0.81 PALB2 2 279 0.72 KRAS 93 317 29.34 NRAS 29 317 9.15 BRAF 32 317 10.09 EIF1AX 14 144 9.72 MSH2 3 275 1.09 MSH3 1 113 0.88 MSH6 6 286 2.10 MLH1 1 317 0.32 MLH3 3 96 3.13 PMS2 1 270 0.37 TP53 12 317 3.79 Citation Format: Muhammad Danyal Ahsan, Emily M. Webster, Sarah R. Levi, Natalie T. Nguyen, Juan R. Cubillos-Ruiz, Evelyn Cantillo, Eloise Chapman-Davis, Melissa K. Frey, Kevin Holcomb. Racial and ethnic differences in the mutational landscape of low-grade serous ovarian cancer. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4258.

Abstract 6522: Improved detection of low frequency mutations in ovarian and endometrial cancers by utilizing a highly accurate sequencing platform

Abstract Ovarian and endometrial cancers come within the top-4 for incident cancers as well as deaths in North American women. Cure rates have not improved in 30 years as high-grade subtypes continue to be diagnosed in Stage III/IV. Attempts at early diagnosis have failed because high-grade cancer cells exfoliate and metastasize while the primary cancer is small and undetectable by existing tests based on imaging and blood-based tumour markers. DOvEEgene (Detecting Ovarian and Endometrial cancers Early using genomics) is a genomic uterine pap test developed by a McGill team to screen and detect these cancers while they are confined to the gynecologic organs and curable by surgery. The test identifies pathogenic somatic mutations in uterine brush samples A high sensitivity error-reducing capture technology (DOvEEgene-SureSelectHS) utilizing duplex sequencing interrogates the exons of 23 genes involved in the development of sporadic and hereditary ovarian and endometrial cancers. We apply a combination of germline gene panel testing on saliva samples with deep duplex sequencing to detect somatic mutations at <0.1% VAF, interrogation of microsatellite loci for instability and low coverage WGS for copy number analysis of uterine brush samples. Currently, DOvEEgene is the only test that can discriminate ovarian and endometrial cancers in peri- and postmenopausal women from benign gynecologic diseases common in that age group. This is important because pathogenic somatic driver mutations are also associated with increasing age and benign disease. DOvEEgene incorporates a deep machine-learning derived classifier that can discriminate the mutational signature of these cancers from benign disease aiming for a sensitivity of 70% and a specificity of 100% in a population with high background mutational burden. Here we tested the Onso system, a highly accurate sequencing technology from PacBio in order to potentially increase sensitivity while driving down sequencing costs by reducing required sequencing depth vs the current NGS standard. We sequenced 15 duplex Illumina sequencing libraries produced using the DovEE assay at PE 100bp mode and compared Onso data in non- duplex sequencing mode as well as duplex sequencing mode to the original duplex sequencing method. Here, we present this comparison and highlight the benefits of high accuracy sequencing for the detection of very low frequency (<0.1%) somatic mutations. Citation Format: Jiannis Ragoussis, Nairi Pezeshkian, Lucy Gilbert. Improved detection of low frequency mutations in ovarian and endometrial cancers by utilizing a highly accurate sequencing platform [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6522.

Tregs are involved in VEGFA/ VASH1-related angiogenesis pathway in ovarian cancer

Vasohibin1 (VASH1) is a kind of vasopressor, produced by negative feedback from vascular endothelial growth factor A (VEGFA). Anti-angiogenic therapy targeting VEGFA is currently the first-line treatment for advanced ovarian cancer (OC), but there are still many adverse effects. Regulatory T cells (Tregs) are the main lymphocytes mediating immune escape function in the tumor microenvironment (TME) and have been reported to influence the function of VEGFA. However, whether Tregs are associated with VASH1 and angiogenesis in TME in OC is unclear. We aimed to explore the relationship between angiogenesis and immunosuppression in the TME of OC. We validated the relationship between VEGFA, VASH1, and angiogenesis in ovarian cancer and their prognostic implications. The infiltration level of Tregs and its marker forkhead box protein 3 (FOXP3) were explored in relation to angiogenesis-related molecules. The results showed that VEGFA and VASH1 were associated with clinicopathological stage, microvessel density and poor prognosis of ovarian cancer. Both VEGFA and VASH1 expression were associated with angiogenic pathways and there was a positive correlation between VEGFA and VASH1 expression. Tregs correlated with angiogenesis-related molecules and indicated that high FOXP3 expression is harmful to the prognosis. Gene set enrichment analysis (GSEA) predicted that angiogenesis, IL6/JAK/STAT3 signaling, PI3K/AKT/mTOR signaling, TGF-β signaling, and TNF-α signaling via NF-κB may be common pathways for VEGFA, VASH1, and Tregs to be involved in the development of OC. These findings suggest that Tregs may be involved in the regulation of tumor angiogenesis through VEGFA and VASH1, providing new ideas for synergistic anti-angiogenic therapy and immunotherapy in OC.

Up-regulation of oxidized low-density lipoprotein receptor 1 correlates with decreased miR-106b-5p, miR-93-5p, miR-3129-5p, miR-199b-3p, and miR-4465, higher recurrence rate, and poor prognosis in ovarian cancer.

MicroRNAs (miRNAs) are widely involved in cell metabolism, and their abnormal expression is involved in the regulation of ovarian cancer development, metastasis, and recurrence. The current study aimed to explore the potential mechanism and prognostic value of miRNAs related to the targeted regulation of oxidized low-density lipoprotein receptor 1 (OLR1) expression in ovarian cancer. A prospective study was conducted including 132 ovarian cancer patients. Patients were followed up for 36 months. The dual-luciferase reporter gene detection was used to verify the targeting relationship between miRNA and OLR1. Cell Counting Kit-8 assay, flow cytometric analysis, transwell migration, and invasion assays were performed to address the malignant biological behaviors of ovarian cancer cells. OLR1 protein and gene expression levels were significantly higher in ovarian cancer tissues and cell lines than in adjacent tissues and normal ovarian epithelial cells. OLR1 depletion facilitated apoptosis and impeded cell proliferation, migration, and invasion in ovarian cancer. Predictive software and dual-luciferase reporter assays showed that miR-106b-5p, miR-93-5p, miR-3129-5p, miR-199b-3p, and miR-4465 targeted OLR1 expression. Functionally, the introduction of miR-106b-5p, miR-93-5p, miR-3129-5p, miR-199b-3p, and miR-4465 mimics abrogated the aggressive phenotype in ovarian cancer cells. Lastly, compared with adjacent tissues, the levels of miR-106b-5p, miR-93-5p, miR-3129-5p, miR-199b-3p, and miR-4465 in cancer tissues were significantly lower (P<0.001). Compared with high miR-106b-5p, high miR-93-5p, high miR-3129-5p, high miR-199b-3p, high miR-4465 group and low OLR1 group, the low miR-106b-5p, low miR-93-5p, low miR-3129-5p, low miR-199b-3p, low miR-4465 group and high OLR1 group have significantly higher recurrence (all P<0.05) and higher mortality (all P<0.05). The identification value of recurrence assessment model [Y = 4.267+0.336*(miR-106b-5p)+0.168*(miR-93-5p)+1.847*(miR-3129-5p)+2.119*(miR-199b-3p)+0.872*(miR-4465)-3.408*(OLR1)] was high with an AUC of 0.918. The prognosis assessment model [Y = 3.914+0.143*(miR-106b-5p)+0.102*(miR-93-5p)+0.115*(miR-3129-5p)+1.369*(miR-199b-3p)+0.186*(miR-4465)-0.334*(OLR1)] also had high identification value with an AUC of 0.934. The combined detection of miR-106b-5p, miR-93-5p, miR-3129-5p, miR-199b-3p, miR-4465, and OLR1 is expected to become a molecular biomarker for the long-term prognostic assessment of ovarian cancer.

The Interaction between Intratumoral Microbiome and Immunity Is Related to the Prognosis of Ovarian Cancer.

Microbiota can influence the occurrence, development, and therapeutic response of a wide variety of cancer types by modulating immune responses to tumors. Recent studies have demonstrated the existence of intratumor bacteria inside ovarian cancer (OV). However, whether intratumor microbes are associated with tumor microenvironment (TME) and prognosis of OV still remains unknown. The RNA-sequencing data and clinical and survival data of 373 patients with OV in The Cancer Genome Atlas (TCGA) were collected and downloaded. According to the knowledge-based functional gene expression signatures (Fges), OV was classified into two subtypes, termed immune-enriched and immune-deficient subtypes. The immune-enriched subtype, which had higher immune infiltration enriched with CD8+ T cells and the M1 type of macrophages (M1) and higher tumor mutational burden, exhibited a better prognosis. Based on the Kraken2 pipeline, the microbiome profiles were explored and found to be significantly different between the two subtypes. A prediction model consisting of 32 microbial signatures was constructed using the Cox proportional-hazard model and showed great prognostic value for OV patients. The prognostic microbial signatures were strongly associated with the hosts' immune factors. Especially, M1 was strongly associated with five species (Achromobacter deleyi and Microcella alkaliphila, Devosia sp. strain LEGU1, Ancylobacter pratisalsi, and Acinetobacter seifertii). Cell experiments demonstrated that Acinetobacter seifertii can inhibit macrophage migration. Our study demonstrated that OV could be classified into immune-enriched and immune-deficient subtypes and that the intratumoral microbiota profiles were different between the two subtypes. Furthermore, the intratumoral microbiome was closely associated with the tumor immune microenvironment and OV prognosis. IMPORTANCE Recent studies have demonstrated the existence of intratumoral microorganisms. However, the role of intratumoral microbes in the development of ovarian cancer and their interaction with the tumor microenvironment are largely unknown. Our study demonstrated that OV could be classified into immune-enriched and -deficient subtypes and that the immune enrichment subtype had a better prognosis. Microbiome analysis showed that intratumor microbiota profiles were different between the two subtypes. Furthermore, the intratumor microbiome was an independent predictor of OV prognosis that could interact with immune gene expression. Especially, M1 was closely associated with intratumoral microbes, and Acinetobacter seifertii could inhibit macrophage migration. Together, the findings of our study highlight the important roles of intratumoral microbes in the TME and prognosis of OV, paving the way for further investigation into its underlying mechanisms.

The sequestosome 1 protein: therapeutic vulnerabilities in ovarian cancer.

Ovarian cancer (OC) is the most deadly tumor that may develop in a woman's reproductive system. It is also one of the most common causes of death among those who have been diagnosed with cancer in women. An adapter protein known as sequestosome 1(SQSTM1) or p62 is primarily responsible for the transportation, degradation, and destruction of a wide variety of proteins. This adapter protein works in conjunction with the autophagy process as well as the ubiquitin proteasome degradation pathway. In addition, the ability of SQSTM1 to interact with multiple binding partners link SQSTM1 to various pathways in the context of antioxidant defense system and inflammation. In this review, we outline the processes underlying the control that SQSTM1 has on these pathways and how their dysregulation contributes to the development of OC. At the final, the therapeutic approaches based on SQSTM1 targeting have been discussed.

Low-dose BPA and its substitute BPS promote ovarian cancer cell stemness via a non-canonical PINK1/p53 mitophagic signaling

The environmental toxicity of bisphenol A (BPA) and its analog like bisphenol S (BPS) have drawn wide attention, but their roles in cancer progression remain controversial. Here, we investigated the effect of BPA/BPS on the development of ovarian cancer. Human internal BPA/BPS exposure levels were analyzed from NHANES 2013–2016 data. We treated human ovarian cancer cells with 0−1000 nM BPA/BPS and found that 100 nM BPA/BPS treatment significantly increased Cancer Stem Cell (CSC) markers expression including OCT4, NANOG and SOX2. Cancer cell stemness evaluation induced by BPA/BPS was notably attenuated by the knockdown of PINK1 or Mdivi-1 treatment. The activation of PINK1 initiated mitophagy by inhibiting p-p53 nuclear translocation in a non-canonical manner. In vivo studies validated that BPA/BPS-exposed mice have higher tumor metastasis incidence compared with the control group, while mitophagy inhibition blocked such a promotion effect. In addition, CSC markers such as SOX2 had been found to be overexpressed in the tumor tissues of BPA/BPS exposure group. Taken together, the findings herein first provide the evidence that environmentally relevant BPA/BPS exposure could enhance ovarian cancer cell stemness through a non-canonical PINK1/p53 mitophagic pathway, raising concerns about the potential population hazards of BPA and other bisphenol analogs.

Frequency and distribution of BRCA1/BRCA2 large genomic rearrangements in Turkish population with breast cancer.

Germline mutations in BRCA1 and BRCA2 genes are mainly responsible for breast and/or ovarian cancer patients. Most of the mutations in these genes are single nucleotide changes or deletions/insertions of small numbers of bases, while a minority of mutations in these genes are large genomic rearrangements (LGRs). The frequency of LGRs in the Turkish population is not clearly known. Also insufficient awareness of the importance of LGRs in breast and/or ovarian cancer development can lead to some disruptions in patient management. So, we aimed to determine the frequency and distribution of the LGRs in the BRCA1/2 genes in the Turkish population. We investigated rearrangements of BRCA genes using multiplex ligation-dependent probe amplification (MLPA) analysis in 1540 patients with a personal and/or family history of breast and/or ovarian cancer or who had familial known large deletion/duplication and applied for segregation. The estimated overall frequency of LGRs in our group was 3,4% (52/1540) with 91% in BRCA1 gene and 9% in BRCA2 gene. 13 different rearrangements were detected (10 BRCA1, 3 BRCA2). To the best our knowledge, BRCA1 exon 1-16 duplication and BRCA2 exon 6 deletion have not been previously reported before. Our study results supported that the detection of rearrangements in BRCA genes is of great importance and it should be planned routinely in patients whose mutations cannot be detected by sequence analysis in screening programs.

Chemerin and Chemokine-like Receptor 1 Expression in Ovarian Cancer Associates with Proteins Involved in Estrogen Signaling

Chemerin, a pleiotropic adipokine coded by the RARRES2 gene, has been reported to affect the pathophysiology of various cancer entities. To further approach the role of this adipokine in ovarian cancer (OC), intratumoral protein levels of chemerin and its receptor chemokine-like receptor 1 (CMKLR1) were examined by immunohistochemistry analyzing tissue microarrays with tumor samples from 208 OC patients. Since chemerin has been reported to affect the female reproductive system, associations with proteins involved in steroid hormone signaling were analyzed. Additionally, correlations with ovarian cancer markers, cancer-related proteins, and survival of OC patients were examined. A positive correlation of chemerin and CMKLR1 protein levels in OC (Spearman's rho = 0.6, p < 0.0001) was observed. Chemerin staining intensity was strongly associated with the expression of progesterone receptor (PR) (Spearman´s rho = 0.79, p < 0.0001). Both chemerin and CMKLR1 proteins positively correlated with estrogen receptor β (ERβ) and estrogen-related receptors. Neither chemerin nor the CMKLR1 protein level was associated with the survival of OC patients. At the mRNA level, in silico analysis revealed low RARRES2 and high CMKLR1 expression associated with longer overall survival. The results of our correlation analyses suggested the previously reported interaction of chemerin and estrogen signaling to be present in OC tissue. Further studies are needed to elucidate to which extent this interaction might affect OC development and progression.

Bidirectional Mendelian randomization study of insulin-related traits and risk of ovarian cancer.

It is well known that the occurrence and development of ovarian cancer are closely related to the patient's weight and various endocrine factors in the body. Mendelian randomization (MR) was used to analyze the bidirectional relationship between insulin related characteristics and ovarian cancer. The data on insulin related characteristics are from up to 5567 diabetes free patients from 10 studies, mainly including fasting insulin level, insulin secretion rate, peak insulin response, etc. For ovarian cancer, UK Biobank data just updated in 2021 was selected, of which the relevant gene data was from 199741 Europeans. Mendelian randomization method was selected, with inverse variance weighting (IVW) as the main estimation, while MR Pleiotropy, MR Egger, weighted median and other methods were used to detect the heterogeneity of data and whether there was multi validity affecting conclusions. Among all insulin related indicators (fasting insulin level, insulin secretion rate, peak insulin response), the insulin secretion rate was selected to have a causal relationship with the occurrence of ovarian cancer (IVW, P < 0.05), that is, the risk of ovarian cancer increased with the decrease of insulin secretion rate. At the same time, we tested the heterogeneity and polymorphism of this indicator, and the results were non-existent, which ensured the accuracy of the analysis results. Reverse causal analysis showed that there was no causal effect between the two (P>0.05). The impairment of the insulin secretion rate has a causal effect on the risk of ovarian cancer, which was confirmed by Mendel randomization. This suggests that the human glucose metabolism cycle represented by insulin secretion plays an important role in the pathogenesis of ovarian cancer, which provides a new idea for preventing the release of ovarian cancer.

Detection and Genotyping of Human Papillomavirus (HPV16/18), Epstein–Barr Virus (EBV), and Human Cytomegalovirus (HCMV) in Endometrial Endometroid and Ovarian Cancers

The purpose of this study was to evaluate the relationship between human papillomavirus (HPV16/18), Epstein-Barr virus (EBV), and human cytomegalovirus (HCMV) infections and the occurrence of ovarian cancer in 48 women, of whom 36 underwent surgery and chemotherapy (group A), 12 in whom surgery was sufficient (group B), and 60 with endometroid endometrial cancer stage G1-G3 (group C), compared to patients in whom the uterus and its appendages were removed for nononcological reasons (control group). The detection of HPV, EBV, and HCMV in tumor tissue and normal tissue was performed using the real-time polymerase chain reaction (RT-PCR) technique. A statistically significantly higher risk of endometrial cancer was noted in patients infected only with HCMV (OR > 1; p < 0.05). In contrast, a significantly higher risk of ovarian cancer in group A was associated with HPV16, HPV18, and EBV (OR > 1; p < 0.05); a significantly higher risk of ovarian cancer in group B was associated with HPV18 and HMCV (OR > 1; p < 0.05). The obtained results suggest that HCMV infection is associated with the development of a stage of ovarian cancer when treatment can be completed with surgery alone. Meanwhile, EBV appears to be responsible for the development of ovarian cancer in more advanced stages.

Molecular mechanism of Wilms’ tumor (Wt1) (+/−KTS) variants promoting proliferation and migration of ovarian epithelial cells by bioinformatics analysis

Epithelial ovarian cancer (EOC) is a gynecological disease with the highest mortality. With the lack of understanding of its pathogenesis, no accurate early diagnosis and screening method has been established for EOC. Studies revealed the multi-faceted function of Wilms’ tumor (Wt1) genes in cancer, which may be related to the existence of multiple alternative splices. Our results show that Wt1 (+KTS) or Wt1 (−KTS) overexpression can significantly promote the proliferation and migration of human ovarian epithelial cells HOSEpiC, and Wt1 (+KTS) effects were more evident. To explore the Wt1 (+/−KTS) variant mechanism in HOSEpiC proliferation and migration and ovarian cancer (OC) occurrence and development, this study explored the differential regulation of Wt1 (+/−KTS) in HOSEpiC proliferation and migration by transcriptome sequencing. OC-related hub genes were screened by bioinformatics analysis to further explore the differential molecular mechanism of Wt1 (+/−KTS) in the occurrence of OC. Finally, we found that the regulation of Wt1 (+/−KTS) variants on the proliferation and migration of HOSEpiC may act through different genes and signaling pathways and screened out key genes and differentially regulated genes that regulate the malignant transformation of ovarian epithelial cells. The implementation of this study will provide new clues for the early diagnosis and precise treatment of OC.

RNA epigenetic modifications in ovarian cancer: The changes, chances, and challenges.

Ovarian cancer (OC) is the most common female cancer worldwide. Patients with OC have high mortality because of its complex and poorly understood pathogenesis. RNA epigenetic modifications, such as m6 A, m1 A, and m5 C, are closely associated with the occurrence and development of OC. RNA modifications can affect the stability of mRNA transcripts, nuclear export of RNAs, translation efficiency, and decoding accuracy. However, there are few overviews that summarize the link between m6 A RNA modification and OC. Here, we discuss the molecular and cellular functions of different RNA modifications and how their regulation contributes to the pathogenesis of OC. By improving our understanding of the role of RNA modifications in the etiology of OC, we provide new perspectives for their use in OC diagnosis and treatment. This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease.

Oncogenic SIRT7 inhibits GATA4 transcriptional activity and activates the Wnt signaling pathway in ovarian cancer

ObjectiveSirtuin-7 (SIRT7) is a class III histone deacetylase that plays an important role in cancer development and frequently overexpressed in carcinomas. In this study, the tumor-supporting role and underlying mechanisms of SIRT7 were characterized in ovarian cancer (OC) aggressiveness. MethodsSIRT7 expression was examined in OC tissues and cells. Interactions among SIRT7, GATA4, Wnt signaling pathway were explored by bioinformatics tools and experimental validations. The effect of SIRT7 and GATA4 on malignant phenotypes of OC cells were examined with gain- and loss-of-function experiments. A nude mouse model of OC was developed to verify the in vitro findings. ResultsIt was noted that SIRT7 was highly expressed in OC tissues and cells. Cell lines with higher SIRT7 expression (OVCAR-3 and OVCAR-8) were used for subsequent in vitro experiments. The experimental data indicated that silencing of SIRT7 suppressed the OC cell proliferation, colony formation, migration, and invasion, and promoted cell senescence, which could be abolished by GATA4 knockdown. Mechanistically, SIRT7 promoted deacetylation of GATA4 and consequently inhibited the transcriptional activity of GATA4. In addition, GATA4 induced OC cell senescence by inhibiting Wnt signaling pathway. Further in vivo experiments substantiated that SIRT7 knockdown or overexpressed GATA4 could effectively inhibit tumor growth of nude mice. ConclusionTaken together, our findings indicated that SIRT7 enhanced development of OC by suppressing GATA4 and activating Wnt signaling pathway, suggesting the potential of SIRT7/GATA4/Wnt axis as a therapeutic target for OC.

Negative effects of endocrine disruptor bisphenol A on ovarian granulosa cells and the protective role of folic acid.

Bisphenol A (BPA) is a widely produced chemical, mostly used in the production of polycarbonate plastics, and can act as an endocrine disruptor. This paper focuses on the different effects of BPA on ovarian granulosa cells. Bisphenol A (BPA) is an endocrine disruptor (ED), widely used as a comonomer or an additive in the plastics industry. It can be found in food and beverage plastic packaging, epoxy resins, thermal paper and other common products. To date, there have only been several experimental studies to have examined how BPA exposure affects human and mammalian follicular granulosa cells (GCs) in vitro and in vivo; the collected evidence data show that BPA negatively affects the GCs by altering steroidogenesis and gene expression, inducing autophagy, apoptosis and cellular oxidative stress through reactive oxygen species production. Exposure to BPA can also lead to abnormally constrained or elevated cellular proliferation and can even reduce cell viability. Therefore, research on EDs such as BPA is important as it provides some important insights into the causes and development of infertility, ovarian cancer and other conditions related to impaired ovarian and GC function. Folic acid, a biologic form of vitamin B9, is a methyl donor that can neutralize the toxic effects of the BPA exposure and is, as a common food supplement, an interesting option for researching its protective role against ubiquitous harmful EDs such as BPA.

Purine Intake and All-Cause Mortality in Ovarian Cancer: Results from a Prospective Cohort Study

Current biological evidence suggests that purine involvement in purine metabolism may contribute to the development and progression of ovarian cancer (OC), but the epidemiological association is currently unknown. A total of 703 newly diagnosed patients with OC aged 18-79 years were included in this prospective cohort study. Utilizing a verified food-frequency questionnaire, the participants' dietary consumption was gathered. Using medical records and ongoing follow-up, the deaths up until 31 March 2021 were determined. To assess the hazard ratios (HRs) and 95% confidence intervals (CIs) of purine intake with OC mortality, Cox proportional-hazard models were utilized. During the median follow-up of 31 months (interquartile: 20-47 months), 130 deaths occurred. We observed an improved survival for the highest tercile of total purine intake compared with the lowest tercile (HR = 0.39, 95% CI = 0.19-0.80; p trend < 0.05), and this protective association was mainly attributed to xanthine intake (HR = 0.52, 95% CI = 0.29-0.94, p trend < 0.05). Additionally, we observed a curving relationship in which OC mortality decreased with total purine intake, and the magnitude of the decrease was negatively correlated with intake (p non-linear < 0.05). Significant inverse associations were also observed in subgroup analyses and sensitivity analyses according to demographic and clinical characteristics. Moreover, we observed that xanthine intake and hypoxanthine intake had a multiplicative interaction with ER and PR expression (p < 0.05), respectively. A high total purine and xanthine intake was linked to a lower risk of OC mortality. Further clarification of these findings is warranted.

Circ_0000471 suppresses the progression of ovarian cancer through mediating mir-135b-5p/dusp5 axis.

Ovarian cancer (OC) is a common gynecologic cancer with high incidence and mortality. We attempted to investigate the role of circular RNA_0000471 (circ_0000471) in OC progression and its associated mechanism. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot assay were conducted to measure RNA and protein expression, respectively. Cell proliferation was analyzed by Cell Counting Kit-8 (CCK8) assay, colony formation assay, and 5-Ethynyl-2'-deoxyuridine (EdU) assay. Cell apoptosis was assessed by flow cytometry. Cell migration and invasion were analyzed by wound healing assay and transwell assay, respectively. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were conducted to verify the target relationships. Xenograft tumor model was established to assess the role of circ_0000471 on tumor growth in vivo. Circ_0000471 expression was down-regulated in OC tissues and cell lines. Circ_0000471 overexpression blocked the proliferation, migration, and invasion and triggered the apoptosis of OC cells. Circ_0000471 served as a molecular sponge for microRNA-135b-5p (miR-135b-5p), and circ_0000471 overexpression-mediated anti-tumor influences in OC cells were largely reversed by the overexpression of miR-135b-5p. Dual specificity phosphatase 5 (DUSP5) was a target of miR-135b-5p, and miR-135b-5p silencing-induced anti-tumor effects were largely counteracted by the interference of DUSP5. Circ_0000471 increased DUSP5 expression by sponging miR-135b-5p in OC cells. Circ_0000471 overexpression restrained the growth of xenograft tumors in vivo. Overexpression of circ_0000471 inhibited OC development by targeting miR-135b-5p/DUSP5 axis, indicating that circ_0000471 may be a new potential target for OC treatment.

Glucose-Regulated Protein 78 Is a Potential Serum and Imaging Marker for Early Detection of Ovarian Cancer.

Understanding malignant transformation associated with ovarian cancer (OVCA) is important to establish early detection tests. This study examined whether expression of glucose-regulated protein 78 (GRP78, marker of cellular stress) increases during OVCA development, and whether GRP78 can be detected by targeted-transvaginal ultrasound (TVUS) imaging. Normal ovaries (n = 10), benign (n = 10) and malignant ovarian tumors at early (n = 8) and late stages (n = 16), hens with and without ovarian tumors at early and late stages (n = 10, each) were examined for GRP78 expression during OVCA development by immunohistochemistry, immunoblotting, gene expression and immunoassay. Feasibility of GRP78-targeted TVUS imaging in detecting early OVCA was examined. Compared with normal ovaries and benign tumors, intensity of GRP78 expression was higher (p < 0.0001) in OVCA patients. Compared with normal (9007.76 ± 816.54 pg/mL), serum GRP78 levels were significantly higher (p < 0.05) in patients with early (12,730.59 ± 817.35 pg/mL) and late-stage OVCA (13,930.12 ± 202.35) (p < 0.01). Compared with normal (222.62 ± 181.69 pg/mL), serum GRP78 levels increased (p < 0.05) in hens with early (590.19 ± 198.18 pg/mL) and late-stage OVCA (1261.38 ± 372.85) (p < 0.01). Compared with non-targeted, GRP78-targeted imaging enhanced signal intensity of TVUS (p < 0.0001). Tissue and serum levels of GRP78 increase in association with OVCA. GRP78 offers a potential serum and imaging marker for early OVCA detection.

LINC00936/microRNA-221-3p Regulates Tumor Progression in Ovarian Cancer by Interacting with LAMA3.

Ovarian cancer remains a leading cause of mortality in women. It is known that long non-coding RNA (lncRNA) controls various biological processes and pathogenesis of many diseases, including cancers. This study aimed to determine whether LINC00936 and microRNA-221-3p (miR-221-3p) influence the laminin alpha 3 chain gene (LAMA3) in the development of ovarian cancer. The expressions of LINC00936, miR-221-3p, and LAMA3 in ovarian cancer and adjacent tissues were assessed. Furthermore, ovarian cancer cells were transfected with vectors with overexpressed LINC00936, miR-221-3p mimic, miR-221-3p inhibitor, and si-LAMA3 to elucidate their functions in ovarian cancer cell proliferation, migration, invasion, angiogenesis, and tumorigenesis. The binding relationship between LINC00936 and miR-221-3p and the relationship between miR-221-3p and LAMA3 were verified to explore the mechanism of action of LINC00936 in ovarian cancer. LINC00936 binds to miR-221-3p as a ceRNA and regulates the expression of LAMA3. LINC00936 and LAMA3 were poorly expressed, while miR-221-3p was highly expressed in ovarian cancer tissues. Over-expression of LINC00936 contributed to decreasing miR- 221-3p expression and increasing LAMA3 expression. LINC00936 overexpression or miR-221- 3p silencing downregulated the levels of PCNA, MMP-2, MMP-9, and VEGF and decreased cell proliferation, migration, invasion, angiogenesis, and ovarian cancer tumorigenesis. Collectively, overexpression of LINC00936 suppressed the development of ovarian cancer by competitively binding to miR-221-3p and controlling LAMA3 expression. These results could serve as a novel theoretical base for the treatment of ovarian cancer.

Research progress of long non-coding RNA in ovarian cancer: a narrative review

Background and Objective: Ovarian cancer (OC) is one of the most lethal malignancies of women around the world. Among all gynecological malignant tumours, most OC patients are diagnosed at advanced stages with a low 5-year survival rate and dim prognosis. Long non-coding RNAs (lncRNAs) are a class of noncoding RNA over 200 nucleotides without protein coding capacity. LncRNAs are involved in different biological processes and form various regulatory networks in different type of cancers. Their aberrant expression plays an important role in the neoplasm and development of OC.