scholarly journals Epigenetic Silencing of miR-33b Promotes Peritoneal Metastases of Ovarian Cancer by Modulating the TAK1/FASN/CPT1A/NF-κB Axis

Cancers ◽  
2021 ◽  
Vol 13 (19) ◽  
pp. 4795
Author(s):  
Xueyu Wang ◽  
Mingo M. H. Yung ◽  
Rakesh Sharma ◽  
Fushun Chen ◽  
Ying-Tung Poon ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Critical Role ◽  
Peritoneal Metastases ◽  
Epigenetic Silencing ◽  
Serous Carcinoma ◽  
Ovarian Cancer Cells ◽  
Epigenetic Alterations ◽  
The Impact

Peritoneal metastases are frequently found in high-grade serous carcinoma (HGSOC) patients and are commonly associated with a poor prognosis. The tumor microenvironment (TME) is a complex milieu that plays a critical role in epigenetic alterations driving tumor development and metastatic progression. However, the impact of epigenetic alterations on metastatic ovarian cancer cells in the harsh peritoneal microenvironment remains incompletely understood. Here, we identified that miR-33b is frequently silenced by promoter hypermethylation in HGSOC cells derived from metastatic omental tumor tissues. Enforced expression of miR-33b abrogates the oncogenic properties of ovarian cancer cells cocultured in omental conditioned medium (OCM), which mimics the ascites microenvironment, and in vivo tumor growth. Of note, restoration of miR-33b inhibited OCM-upregulated de novo lipogenesis and fatty acid β-oxidation in ovarian cancer cells, indicating that miR-33b may play a novel tumor suppressor role in the lipid-mediated oncogenic properties of metastatic ovarian cancer cells found in the omentum. Mechanistic studies demonstrated that miR-33b directly targets transforming growth factor beta-activated kinase 1 (TAK1), thereby suppressing the activities of fatty acid synthase (FASN) and carnitine palmitoyltransferase 1A (CPT1A) in modulating lipid metabolic activities and simultaneously inhibiting the phosphorylation of NF-κB signaling to govern the oncogenic behaviors of ovarian cancer cells. Thus, our data suggest that a lipid-rich microenvironment may cause epigenetic silencing of miR-33b, which negatively modulates ovarian cancer peritoneal metastases, at least in part, by suppressing TAK1/FASN/CPT1A/NF-κB signaling.

scholarly journals CircASH2L Promotes Ovarian Cancer Tumorigenesis, Angiogenesis, and Lymphangiogenesis by Regulating the miR-665/VEGFA Axis as a Competing Endogenous RNA

2020 ◽  
Vol 8 ◽  
Author(s):  
Jinxin Chen ◽  
Xiaocen Li ◽  
Lu Yang ◽  
Mengmeng Li ◽  
Ye Zhang ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Molecular Mechanisms ◽  
Critical Role ◽  
Gynecologic Cancer ◽  
Luciferase Reporter ◽  
Circular Rnas ◽  
Ovarian Cancer Cells ◽  
Western Blots ◽  
The Impact

Ovarian cancer is the leading cause of gynecologic cancer-related deaths. Emerging research has revealed a close relationship between circular RNAs (circRNAs) and ovarian cancer development, metastasis, and prognosis. The objective of our research was to further explore the relationship between circASH2L and ovarian cancer. Quantitative real-time polymerase chain reaction was used to detect the differential expression of circRNAs between normal ovaries and ovarian cancer tissues. The impact of circASH2L on the proliferation, invasion, and tumorigenicity of ovarian cancer cells was evaluated using gain- and loss-of-function experiments. The molecular mechanisms of circASH2L function were investigated using bioinformatics analysis, RNA fluorescence in situ hybridization, western blots, and dual-luciferase reporter assays. The results showed that circASH2L was remarkably upregulated in ovarian cancer. The invasion and growth of ovarian cancer cells were suppressed by circASH2L knockdown in vitro, and downregulation of circASH2L restrained both angiogenesis and lymphangiogenesis of tumor xenografts in vivo. Furthermore, circASH2L was mostly distributed in the cytoplasm, where it competes with vascular endothelial growth factor A (VEGFA) for binding to miR-665. These findings indicate that circASH2L has an oncogenic function in ovarian cancer. In conclusion, circASH2L plays a critical role in regulating ovarian cancer cell tumorigenesis, angiogenesis, and lymphangiogenesis through the miR-665/VEGFA axis and, therefore, is a possible candidate target for ovarian cancer treatment.

scholarly journals Expression of Fatty Acid Synthase Depends on NAC1 and Is Associated with Recurrent Ovarian Serous Carcinomas

2010 ◽  
Vol 2010 ◽  
pp. 1-12 ◽  
Author(s):  
Stefanie M. Ueda ◽  
Kai Lee Yap ◽  
Ben Davidson ◽  
Yuan Tian ◽  
Vivek Murthy ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Fatty Acid Synthase ◽  
Dominant Negative ◽  
Serous Carcinoma ◽  
Ovarian Cancer Cells ◽  
Primary Tumors ◽  
Ovarian Serous Carcinoma ◽  
Skov3 Cells

Our previous reports demonstrated that NAC1, a BTB/POZ domain-containing nuclear protein, upregulates in recurrent ovarian serous carcinoma and participates in developing drug resistance in cancer cells. The current study applies quantitative proteomics to identify the proteins controlled by NAC1 by comparing the proteomes of SKOV3 cells with and without expression of a dominant negative NAC1 construct, N130. From the proteins that are downregulated by N130 (upregulated by NAC1), we chose to further characterize fatty acid synthase (FASN). Similar to change in protein level, the FASN transcript level in SKOV3 cells was significantly reduced by N130 induction or by NAC1 knockdown. Immunohistochemistry showed that NAC1 and FASN immunointensities in ovarian serous carcinoma tissues had a highly significant correlation (P<.0001). Moreover, we found that recurrent serous carcinomas exhibited higher FASN immunointensities than their matched primary tumors (P<.001). Multivariate analysis showed that an FASN staining score of >1 in serous carcinomas was associated with a worse overall survival time (P<.01). Finally, C93, a new FASN inhibitor, induced massive apoptosis in carboplatin/paclitaxel resistant ovarian cancer cells. In conclusion, we show that NAC1 is essential for FASN expression in ovarian serous carcinomas and the expression of FASN significantly correlates with tumor recurrence and disease aggressiveness. The dependence of drug resistant tumor cells on FASN suggests a potential application of FASN-based therapeutics for recurrent ovarian cancer patients.

scholarly journals PAX8 expression in high-grade serous ovarian cancer positively regulates attachment to ECM via Integrin β3

2019 ◽  
Vol 19 (1) ◽  
Author(s):  
Amata Amy Soriano ◽  
Tiziana de Cristofaro ◽  
Tina Di Palma ◽  
Serena Dotolo ◽  
Priyanka Gokulnath ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Fallopian Tube ◽  
Critical Role ◽  
Serous Carcinoma ◽  
Secretory Cells ◽  
Ovarian Cancer Cells ◽  
High Grade ◽  
Adhesion Properties ◽  
Pax8 Expression

Abstract Background Ovarian cancer is the third most common cause of death among gynecologic malignancies worldwide. Understanding the biology and molecular pathogenesis of ovarian epithelial tumors is key to developing improved prognostic indicators and effective therapies. We aimed to determine the effects of PAX8 expression on the migrative, adhesive and survival capabilities of high-grade serous carcinoma cells. Methods PAX8 depleted Fallopian tube secretory cells and ovarian cancer cells were generated using short interfering siRNA. Anoikis resistance, cell migration and adhesion properties of PAX8 silenced cells were analyzed by means of specific assays. Chromatin immunoprecipitation (ChIP) was carried out using a PAX8 polyclonal antibody to demonstrate that PAX8 is able to bind to the 5′-flanking region of the ITGB3 gene positively regulating its expression. Results Here, we report that RNAi silencing of PAX8 sensitizes non-adherent cancer cells to anoikis and affects their tumorigenic properties. We show that PAX8 plays a critical role in migration and adhesion of both Fallopian tube secretory epithelial cells and ovarian cancer cells. Inhibition of PAX8 gene expression reduces the ability of ovarian cancer cells to migrate and adhere to the ECM and specifically to fibronectin and/or collagen substrates. Moreover, loss of PAX8 strongly reduces ITGB3 expression and consequently the correct expression of the αvβ3 heterodimer on the plasma membrane. Conclusions Our results demonstrate that PAX8 modulates the interaction of tumor cells with the extracellular matrix (ECM). Notably, we also highlight a novel pathway downstream this transcription factor. Overall, PAX8 could be a potential therapeutic target for high-grade serous carcinoma.

scholarly journals SCD1/FADS2 fatty acid desaturases equipoise lipid metabolic activity and redox-driven ferroptosis in ascites-derived ovarian cancer cells

2021 ◽  
Author(s):  
Yang XUAN ◽  
Mingo YUNG ◽  
Fushun Chen ◽  
Huogang WANG ◽  
Wai-Sun CHAN ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Fatty Acid ◽  
Unsaturated Fatty Acids ◽  
Malignant Ascites ◽  
Peritoneal Metastases ◽  
Ovarian Cancer Cells ◽  
Platinum Resistance ◽  
Fatty Acid Desaturases ◽  
Genetic Ablation ◽  
Metabolic Activities

Abstract Malignant ascites in peritoneal metastases is a lipid-enriched microenvironment and is frequently involved in the poor prognosis of epithelial ovarian cancer (EOC). However, the detailed mechanisms underlying ovarian cancer (OvCa) cells dictating their lipid metabolic activities in promoting tumor progression remain elusive. Here, we report that two critical fatty acid desaturases, stearoyl-CoA desaturase-1 (SCD1) and acyl-CoA 6-desaturase (FADS2), are aberrantly upregulated, accelerating lipid metabolic activities and tumor aggressiveness of ascites-derived OvCa cells. Lipidomic analysis revealed that the elevation of unsaturated fatty acids (UFAs) is positively associated with SCD1/FADS2 levels and the oncogenic capacities of OvCa cells. In contrast, pharmaceutical inhibition and genetic ablation of SCD1/FADS2 retarded tumor growth, suppressed cancer stem cell (CSC) formation and reduced platinum resistance in OvCa cells. Mechanistically, inhibition of SCD1/FADS2 directly downregulated GPX4 and the GSH/GSSG ratio, causing disruption of the cellular redox balance and subsequent iron-mediated lipid peroxidation in ascites-derived OvCa cells. Hence, combinational treatment with SCD1/FADS2 inhibitors and cisplatin synergistically repressed tumor cell dissemination, providing a promising chemotherapeutic strategy against EOC platinum resistance and peritoneal metastases.

scholarly journals Photodynamic Therapy Using a New Folate Receptor-Targeted Photosensitizer on Peritoneal Ovarian Cancer Cells Induces the Release of Extracellular Vesicles with Immunoactivating Properties

2020 ◽  
Vol 9 (4) ◽  
pp. 1185 ◽  
Author(s):  
Martha Baydoun ◽  
Olivier Moralès ◽  
Céline Frochot ◽  
Colombeau Ludovic ◽  
Bertrand Leroux ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Immune Response ◽  
Photodynamic Therapy ◽  
Cancer Cells ◽  
Tumor Cells ◽  
Extracellular Vesicles ◽  
Immune Cells ◽  
Surgical Techniques ◽  
Ovarian Cancer Cells ◽  
The Impact

Often discovered at an advanced stage, ovarian cancer progresses to peritoneal carcinoma, which corresponds to the invasion of the serosa by multiple tumor implants. The current treatment is based on the combination of chemotherapy and tumor cytoreduction surgery. Despite the progress and standardization of surgical techniques combined with effective chemotherapy, post-treatment recurrences affect more than 60% of women in remission. Photodynamic therapy (PDT) has been particularly indicated for the treatment of superficial lesions on large surfaces and appears to be a relevant candidate for the treatment of microscopic intraperitoneal lesions and non-visible lesions. However, the impact of this therapy on immune cells remains unclear. Hence, the objective of this study is to validate the efficacy of a new photosensitizer [pyropheophorbide a-polyethylene glycol-folic acid (PS)] on human ovarian cancer cells and to assess the impact of the secretome of PDT-treated cells on human peripheral blood mononuclear cells (PBMC). We show that PS, upon illumination, can induce cell death of different ovarian tumor cells. Furthermore, PDT using this new PS seems to favor activation of the immune response by inducing the secretion of effective cytokines and inhibiting the pro-inflammatory and immunosuppressive ones, as well as releasing extracellular vesicles (EVs) prone to activating immune cells. Finally, we show that PDT can activate CD4+ and CD8+ T cells, resulting in a potential immunostimulating process. The results of this pilot study therefore indicate that PS-PDT treatment may not only be effective in rapidly and directly destroying target tumor cells but also promote the activation of an effective immune response; notably, by EVs. These data thus open up good prospects for the treatment of micrometastases of intraperitoneal ovarian carcinosis which are currently inoperable.

Critical role of SEMA5A expression in invasion and metastasis of ovarian cancer cell

2014 ◽  
Vol 2 (4) ◽  
pp. 247-259
Keyword(s):  
Ovarian Cancer ◽  
Cancer Cells ◽  
Cancer Cell ◽  
Ovarian Cancer Cell ◽  
Critical Role ◽  
Migration And Invasion ◽  
Ovarian Cancer Cells ◽  
Cancer Tissue ◽  
Invasion And Metastasis

Semaphorins are a large family of genes involved in the development and morphogenesis of the nervous system. SEMA5A has been reported as a bi-functional molecule, acting as both oncogene and tumor suppressor in different types of cancer. High expression levels of SEMA5A and its receptor, Plexin-B3, were associated with aggressiveness in pancreatic and prostate cancers. Our previous study in ovarian cancer metastasis indicates that FAK knock-down can suppress ovarian cancer cells migration and invasion. We hypothesized that SEMA5A expression promotes ovarian cancer invasion and metastasis. We investigated the expression of SEMA5A in patients with metastatic ovarian cancer (n = 43), localized tumor (n = 37) and normal ovarian tissue (n = 12) from non-malignant diseases as control with different histopathological characteristics. For Silencing of SEMA5A in vitro, we treated human ovarian cancer cells (OVCAR-3, A2780/CP70) with miR-27a and miR-27b. We observed significantly higher expression of SEMA5A protein (P= 0.001) in metastatic ovarian cancer tissue associated with poor overall survival outcomes compared to localized ovarian cancer and control. In vitro silencing of SEMA5A reduced migration and invasion of ovarian cancer cell. Our data offer opportunities for the therapeutic modulation and biomarker of metastatic ovarian cancer.

Relationship of miR-101 and targeted epigenetic silencing of EzH2 on cell growth and invasiveness in ovarian cancer cells.

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. e15538-e15538
Author(s):  
R. B. Batchu ◽  
A. Semaan ◽  
S. M. Seward ◽  
A. Qazi ◽  
S. Chamala ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cell Growth ◽  
Cancer Cells ◽  
Epigenetic Silencing ◽  
Ovarian Cancer Cells ◽  
Relationship Of

scholarly journals Fatty Acid Synthase Inhibition Activates AMP-Activated Protein Kinase in SKOV3 Human Ovarian Cancer Cells

2007 ◽  
Vol 67 (7) ◽  
pp. 2964-2971 ◽  
Author(s):  
Weibo Zhou ◽  
Wan Fang Han ◽  
Leslie E. Landree ◽  
Jagan N. Thupari ◽  
Michael L. Pinn ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Fatty Acid ◽  
Protein Kinase ◽  
Cancer Cells ◽  
Fatty Acid Synthase ◽  
Ovarian Cancer Cells ◽  
Human Ovarian Cancer ◽  
Amp Activated Protein Kinase

scholarly journals Acyl-CoA Medium-Chain Synthetase-3 Promotes Chemosensitivity of Ovarian Cancer through the Inhibition of PI3K/AKT Signaling Pathway

2021 ◽  
Author(s):  
Yuanyuan An ◽  
Hua Duan
Keyword(s):  
Ovarian Cancer ◽  
Fatty Acid ◽  
Cancer Cells ◽  
Signaling Pathway ◽  
Fatty Acid Metabolism ◽  
Acid Metabolism ◽  
Immune Status ◽  
Akt Signaling ◽  
Ovarian Cancer Cells ◽  
Akt Signaling Pathway

Abstract Introduction: Dysregulation of fatty acid metabolism often occurs in tumor, which mainly constitutes of fatty acid synthesis and oxidation. In recent years, studies found that fatty acid metabolism participated in regulation of tumor immune microenvironment, which further influenced the progress of cancer. Thus, it is important to explore the key fatty acid metabolism-related molecules, which not only affects the prognosis of ovarian cancer, but also shows a close correlation with immune microenvironment of cancer.Methods: Database from TCGA was used to explore the fatty acid metabolism-related molecules, which correlated with the prognosis of ovarian cancer using univariate and multivariate cox proportional regression model. Nomogram was constructed to predict the prognostic probability based on ACSM3 and clinicopathological parameters. GDSC database was used to investigate the chemosensitivity of ovarian cancer cells. The correlation between ACSM3 and immune status of ovarian cancer was analyzed by TIMER and TISIDB online tools. In addition, CCK8 assay was used to investigate the chemosensitivity of ovarian cancer cells, real time-PCR and western blot were used to investigate the expression of chemoresistance-related genes.Results: ACSM3 worked as an independent favorable prognostic molecule through univariate and multivariate cox regression analysis. For the use in clinical, nomogram was constructed, and higher expression of ACSM3 showed better prognosis. We found that ACSM3 could regulate PI3K/AKT signaling, and GDSC database showed that PI3K/AKT inhibitor could promote the chemosensitivity of ovarian cancer cells. In addition, the expression of ACSM3 showed significantly correlated with the immune status of ovarian cancer. In vitro experiments showed that ACSM3 can promote the chemosensitivity of ovarian cancer cells by inhibiting PI3K/AKT signaling pathway.Conclusion: Our results showed that ACSM3 acted as a favorable prognostic-related biomarker for ovarian cancer, which could promote chemosensitivity of ovarian cancer through inhibiting PI3K/AKT signaling pathway. This might be due to participate in regulating immune status of ovarian cancer microenvironment.

scholarly journals ES-2 Ovarian Cancer Cells Present a Genomic Profile Inconsistent with their Reported History

2020 ◽  
Author(s):  
Eric J. Devor ◽  
Jace R. Lapierre ◽  
Kimberly K. Leslie ◽  
David P. Bender
Keyword(s):  
Ovarian Cancer ◽  
Cell Carcinoma ◽  
Cancer Cells ◽  
Clear Cell ◽  
Clear Cell Carcinoma ◽  
Serous Carcinoma ◽  
Ovarian Cancer Cells ◽  
African American Patient ◽  
American Patient ◽  
Carcinoma Of The Ovary

Abstract Objective: ES-2 ovarian cancer cells have long been reported to have originated from a primary clear cell carcinoma of the ovary presenting in a 47 year-old African American patient. Two recent publications have offered evidence calling both of these characteristics into question. Our objective was to further study this cell line using quantitative real-time PCR (qPCR) and mitochondrial DNA (mtDNA) sequencing in order to confirm or refute these inconsistencies.Results: qPCR assays on two characteristic loci, hepatocyte nuclear factor 1β (NHF-1β) and glutathione peroxidase 3 (GPX3), suggest that ES-2 are unusual clear cell carcinoma cells that appear more like high grade serous carcinoma than clear cell. Further, mtDNA haplotyping places the ancestral origin of the patient’s lineage in the Middle East or Europe and not Africa. These results are consistent with and support the conclusions of the two recent publications.

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