The role of promoter DNA methylation of six cancer-associated miRNA genes in ovarian cancer development and progression

DNA methylation of promoter CpG islands and interactions between microRNAs and messenger RNAs of target genes are considered two crucial mechanisms for gene and pathway deregulation in malignant tumors. Methylation was analyzed for the large group of tumor-suppressor microRNA genes in various malignancies, but in ovarian tumors, it was not studied extensively yet. Our goal was to identify novel microRNA genes with aberrant methylation in epithelial ovarian cancer and assess contribution of promoter methylation of these genes to ovarian cancer development and progression. Therefore, DNA methylation of six microRNA genes (MIR-9-1, MIR-9-3, MIR-132, MIR-148a, MIR-191, MIR-212) was analyzed using a representative set of 54 paired (tumor/normal) ovarian tissue samples and methylation-specific PCR. The methylation frequencies of four of the examined genes (MIR-9-1, MIR-9-3, MIR-132, MIR-148a) were significantly higher in tumor samples in comparison with matched histologically normal samples: 2057 % vs 4-9 % (p ≤ 0.01, Fisher’s exact test). Conversely, hypomethylation was revealed for MIR-191: 13 % vs 59 %, p ≤ 0.01. We showed strong association of MIR-9-1 and MIR-9-3 hypermethylation with advanced III/IV clinical stages, low differentiation, high tumor sizes (p ≤ 0.05), and the presence of lymph node metastases on the level of a trend. Besides, we observed the dependence of MIR-191 hypomethylation on the ovarian tumor cell differentiation (p ≤ 0.05). Thus, our findings provide the evidence on the considerable contribution of aberrant methylation of five microRNA genes to ovarian cancer development and progression, and allow us to suggest novel potential biomarkers.