Expression and promotor hypermethylation of miR-34a in the various histological subtypes of ovarian cancer

Abstract

BackgroundAn increasing body of evidence shows that miR-34 family has tumor suppressive properties mediating apoptosis, cell cycle arrest and senescence. In ovarian cancer, miR34 family members were found to be under expressed. Particularly miR-34a has been revealed to be a direct transcriptional target of p53 which is frequently mutated in epithelial ovarian carcinomas especially in high grade serous cancer. Moreover, methylation of miR-34a CpG Islands was found to down-regulate miR-34a expression. The aim of this study was to investigate the clinical relevance of mir34a as well as its promoter methylation in a subset of 133 ovarian cancers with a special focus on the p53 mutation status, the dualistic type I and type II ovarian cancer model and the different histotypes.MethodsOne hundred thirty-three epithelial ovarian cancers and 8 samples of healthy ovarian surface epithelium were retrospectively analysed for miR-34a expression with quantitative real-time reverse transcription PCR (qRT-PCR). Gene-specific DNA methylation was evaluated with MethyLight technique.ResultsSignificantly lower miR-34a expression was found in ovarian cancers than in healthy ovarian epithelium (p = 0.002). The expression of miR-34a was found lower in type II than in type I cancers (p = 0.037), in p53 mutated as compared to p53 wild type cancers (p = 0.003) and in high grade compared to in low grade cancers (p = 0.028). In multivariate COX regression model low expressing miR-34a cancers exhibited a reduced PFS (p = 0.039) and OS (p = 0.018). In serous cancers low miR-34a levels showed a worse OS confirmed also in multivariate analysis (p = 0.022). miR-34a promoter methylation was found higher in type II cancers than in type I (p = 0.006). mir34a expression and promoter methylation showed an inverse correlation in cancer samples (p = 0.05).ConclusionWe demonstrated a clinical independent role of miR-34a in epithelial ovarian cancers. Moreover, we corroborated the correlation between miR-34a expression and its promoter methylation in a large set of ovarian cancers. The inverse association between miR-34a expression and grading, p53 mutation status and dualistic tumor type classification, together with its prognostic relevance may underline the tumor-suppressive character of miR-34a in ovarian cancer.

Are microRNAs true sensors of ageing and cellular senescence?

“…In the temporal cortex of Alzheimer’s disease (AD) patients, a profile of six miRNAs involved in the regulation of a myelination pathway were found to be downregulated by hypermethylation of their CpG sites (Villela et al, 2016). Additionally, the miR-34a gene has been shown to be hypermethylated in ovarian cancer cells, indicating that its downregulation through epigenetics could promote the cancerous phenotype of the cells (Schmid et al, 2016). In a fetal alcohol syndrome model in mice, fetal exposure to alcohol was shown to alter DNA methylation in such a way that upregulated the expression of miRNAs commonly seen in neurological and cognitive deficits (Laufer et al, 2013).…”

“…By investigating a specific miRNA profile for breast cancer, miRNAs could potentially be tested for diagnostic purposes. The expression of miR-34a in ovarian cancer cells is controlled by hypermethylation of promoter CpG sites (Schmid et al, 2016). Epigenetic silencing of miR-34a through the hypermethylation could lead to cancerous conditions.…”

Antitumor activity of miR-34a in peritoneal mesothelioma relies on c-MET and AXL inhibition: persistent activation of ERK and AKT signaling as a possible cytoprotective mechanism

“…Its expression has been found to be decreased in a variety of human tumors [5] due to DNA copy number loss or epigenetic silencing through aberrant CpG methylation [6, 7]. Results of studies where the expression of miR-34a was manipulated in human tumor experimental models clearly showed that the miRNA acts as a tumor suppressor by regulating highly relevant processes such as proliferation, cell cycle, apoptosis, invasion, and metastasis [8].…”

An Information Entropy-based Method to Detect microRNA Regulatory Module

“…Some studies on CXCL12 and RBBP8 suggest that they are associated with tumor cell migration and invasion [36], [37]. Some recent studies have shown that miR-34 plays an important role in the process of ovarian cancer [38], [39]. The experiment results confirmed that selected genes and miRNAs of MRMs are highly associated with patient survival.…”