Global methylation profiling in serous ovarian cancer is indicative for distinct aberrant DNA methylation signatures associated with tumor aggressiveness and disease progression

Keita, Mamadou; Wang, Zhiqiang; Pelletier, Jean‐François; Bachvarova, Magdalena; Plante, Marie; Grégoire, Jean; Renaud, Marie-Claude; Mes-Masson, Anne-Marie; Paquet, Éric R.; Bachvarov, Dimcho

doi:10.1016/j.ygyno.2012.11.036

Cited by 51 publications

(64 citation statements)

References 37 publications

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“…Constitutive activation of STAT3, which has been detected in several cancers including ovarian cancer, can lead to cellular transformation and tumorigenesis [26]. Furthermore, STAT3 activation is correlated with disease stage, lymph node metastasis, drug resistance and poor survival in ovarian cancer [27,28,29].…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-302b Suppresses Human Epithelial Ovarian Cancer Cell Growth by Targeting RUNX1

Yin

Yang

et al. 2014

Cell Physiol Biochem

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Background: The microRNA (miR)-302 family functions as a tumor suppressor in human cancer. However, its role in epithelial ovarian carcinoma (EOC) remains unknown. Here, we investigated the role of miR-302b and its target gene RUNX1 in EOC. Methods: The expression levels of miR-302b and RUNX1 were assessed by quantitative real-time PCR and western blotting. The effects of ectopic expression of miR-302b were evaluated by the MTT assay, colony forming assay and flow cytometry. RUNX1 was identified as a target of miR-302b and their interaction was confirmed by luciferase activity assays, RUNX1 silencing and overexpression of a RUNX1 mutant construct lacking the 3′UTR. The effect of miR-302b on the suppression of tumor growth was investigated in vivo in a xenograft mouse model. Results: MiR-302b levels were markedly decreased in EOC specimens. Ectopic expression of miR-302b in EOC cells inhibited cell proliferation and colony formation, induced G0/G1 arrest, and promoted apoptosis. RUNX1 was identified as a direct target of miR-302b, and knockdown of RUNX1 inhibited cell growth in a manner similar to miR-302b overexpression, whereas introduction of a 3′UTR mutant of RUNX1 reversed the suppressive effect of miR-302b. Furthermore, miR-302b overexpression led to the inactivation of the STAT3 signaling pathway in EOC cells and inhibited tumor growth in a xenograft mouse model. Conclusions: MiR-302b functions as a tumor suppressor in EOC by targeting RUNX1 and modulating the activity of the STAT3 signaling pathway.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-302b Suppresses Human Epithelial Ovarian Cancer Cell Growth by Targeting RUNX1

Yin

Yang

et al. 2014

Cell Physiol Biochem

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“…Many smaller studies of fewer HGS samples and CpG sites, often focusing on known or suspected tumor suppressor genes (TSGs), have likewise reported lists of hypermethylated sites (ranging from 50 to 500) [39,51–53]. Again there is poor overlap in the reported genes, and inconsistency in the estimated frequency of tumors found to be hypermethylated.…”

Section: Methylation Patterns In Ovarian Cancermentioning

confidence: 99%

DNA methylation changes in epithelial ovarian cancer histotypes

Earp

Cunningham

2015

Genomics

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Survival after a diagnosis of ovarian cancer has not improved, and despite histological differences, treatment is similar for all cases. Understanding the molecular basis for ovarian cancer risk and prognosis is fundamental, and to this end much has been gleaned about genetic changes contributing to risk, and to a lesser extent, survival. There’s considerable evidence for genetic differences between the four pathologically defined histological subtypes; however, the contribution of epigenetics is less well documented. In this report, we review alterations in DNA methylation in ovarian cancer, focusing on histological subtypes, and studies examining the roles of methylation in determining therapy response. As epigenetics is making its way into clinical care, we review the application of cell free DNA methylation to ovarian cancer diagnosis and care. Finally, we comment on recurrent limitations in the DNA methylation literature for ovarian cancer, which can and should be addressed to mature this field.

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“…3A and Supplementary Table S2). Functional association of specific histone marks with gene expression was identified, whereby K4 enriched genes were expressed at high levels, those with K9 or K27 marks at low levels, bivalent K4-K9 or K4-K27 marks at moderate to high levels, while genes carrying bivalent K9-K27 (22) or trivalent K4-K9-K27 (39) marks were repressed (Fig. 3B and Supplementary Table S3).…”

Section: Fbn1 Papss2 and Ptgis As Components Of A Seovca Gene Exprementioning

confidence: 99%

“…Ovarian cancer, the most lethal among gynecologic malignancies, is associated with late diagnosis, rapidly advancing disease, and frequent, aggressive post-therapeutic recurrence (16,17). Altered CpG methylation, identified as an early event in epithelial ovarian cancer pathogenesis (18)(19)(20)(21)(22), complements histone methylations in modulating biologic functions in the disease (23,24). In the current study, we studied these epigenetic mechanisms in correlation with altered gene expression in an in vitro progression model of serous epithelial ovarian cancer (25).…”

Section: Introductionmentioning

confidence: 97%

Evaluation of Epigenetic Drug Targeting of Heterogenous Tumor Cell Fractions Using Potential Biomarkers of Response in Ovarian Cancer

Singh

Chandra

Bapat

2015

Clinical Cancer Research

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Purpose: Resolution of aberrant epigenetic changes leading to altered gene expression during transformation and tumor progression is pertinent for mechanistic understanding of disrupted pathways in cancer. Such changes provide for biomarkers that can be applied in drug screening and improved disease management. Experimental Design: Genome-wide profiling and analyses of promoter DNA methylation, histone modifications, and gene expression of an in vitro progression model of serous ovarian adenocarcinoma were carried out. Similar in silico analyses and comparison of methylation and gene expression of early- and late-grade ovarian cancer samples in The Cancer Genome Atlas assigned a clinical relevance to our study. Candidate biomarkers were evaluated for epigenetic drug treatments in experimental animal models on a background of differing tumor cell responses arising from intratumor heterogeneity. Results: Differentially regulated genes during tumor progression were identified through the previously mentioned analyses as candidate biomarkers. In examining the tumor suppressor PTGIS as a potential biomarker for treatment with either 5-Aza-dC or TSA, 5-Aza-dC effectively stabilized cell cycling, restricted genetic instability, and derepressed PTGIS expression, while TSA led to emergence of drug-resistant progenitors lacking PTGIS expression. Profiling MEST and RXRγ for curcumin and CBB1007, respectively, indicated an inability of curcumin and CBB1007 in restricting residual tumor regenerative capabilities. Conclusions: Our study provides novel insights into epigenetic regulation in ovarian cancer progression and potential biomarkers for evaluating efficacy of epigenetic drugs in restricting residual tumor regeneration. Such approaches may assign a new functional interpretation of drug efficacy and cell tumor responses in ovarian cancer. Clin Cancer Res; 21(22); 5151–63. ©2015 AACR.

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Global methylation profiling in serous ovarian cancer is indicative for distinct aberrant DNA methylation signatures associated with tumor aggressiveness and disease progression

Cited by 51 publications

References 37 publications

MicroRNA-302b Suppresses Human Epithelial Ovarian Cancer Cell Growth by Targeting RUNX1

MicroRNA-302b Suppresses Human Epithelial Ovarian Cancer Cell Growth by Targeting RUNX1

DNA methylation changes in epithelial ovarian cancer histotypes

Evaluation of Epigenetic Drug Targeting of Heterogenous Tumor Cell Fractions Using Potential Biomarkers of Response in Ovarian Cancer

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