DNA methylation-regulated microRNA pathways in ovarian serous cystadenocarcinoma: A meta-analysis

Epigenetic regulation has been linked to the initiation and progression of cancer. Aberrant expression of microRNAs (miRNAs) is one such mechanism that can activate or silence oncogenes (OCGs) and tumor suppressor genes (TSGs) in cells. A growing number of studies suggest that miRNA expression can be regulated by methylation modification, thus triggering cancer development. However, there is no comprehensive in silico study concerning miRNA regulation by direct DNA methylation in cancer. Ovarian serous cystadenocarcinoma (OSC) was therefore chosen as a tumor model for the present work. Twelve batches of OSC data, with at least 35 patient samples in each batch, were obtained from The Cancer Genome Atlas (TCGA) database. The Spearman rank correlation coefficient (SRCC) was used to quantify the correlation between the CpG DNA methylation level and miRNA expression level. Meta-analysis was performed to reduce the effects of biological heterogeneity among different batches. MiRNA-target interactions were also inferred by computing SRCC and meta-analysis to assess the correlation between miRNA expression and cancer-associated gene expression and the interactions were further validated by a query against the miRTarBase database. A total of 26 potential epigenetic-regulated miRNA genes that can target OCGs or TSGs in OSC were found to show biological relevance between DNA methylation and miRNA gene expression. Furthermore, some of the identified DNA-methylated miRNA genes; for instance, the miR-200 family, were previously identified as epigenetic-regulated miRNAs and correlated with poor survival of ovarian cancer. We also found that several miRNA target genes, BTG3, NDN, HTRA3, CDC25A, and HMGA2 were also related to the poor outcomes in ovarian cancer. The present study proposed a systematic strategy to construct highly confident epigenetic-regulated miRNA pathways for OSC. The findings are validated and are in line with the literature. The inclusion of direct DNA methylated miRNA events may offer another layer of explanation that along with genetics can give a better understanding of the carcinogenesis process.

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