Exploring the potential relevance of microRNAs targeting the ARVC-related gene interaction network to cancer: an in silico testing hypothesis

Arrhythmogenic Right Ventricular Cardiomyopathy (ARVC) is a genetic disorder of the myocardium. Mutations in the PKP2, DSP, DSG2, DSC2, JUP, TMEM43, PLN and DES genes which encode proteins of the cardiac desmosome have been linked to the disease yet, the incomplete penetrance and variable expressivity of these genes'variants have also suggested a role for body activity and myocardial inflammation. Information about cancer predisposition in patients with cardiac-associated genetic variants is scarce and data with respect to the role of cardiac desmosomal proteins in cancer development and/or progression have been limited. Considering the well-established association between various genetic diseases and cancer susceptibility as well as the importance of microRNAs (miRNAs) regulation in malignancy, in this study we aimed at exploring the potential relevance of transcriptional and post-transcriptional regulators of ARVC-related genes in cancer. To evaluate this hypothesis, we used seven bioinformatic software tools, namely BioGRID, dbDEMC, FunRich, GeneCodis, GeneMANIA, RNADisease and STRING. We found that the functional interaction network of the eight genes with substantial evidence of ARVC causality comprises of 432 unique genes. Three hundred three miRNAs were predicted to regulate the expression of the network components. Enrichment analysis for Transcription Factor (TF) and Biological Pathways (BP) ontologies of the predicted miRNAs pointed to cancer-associated biomolecules and processes. TF set analysis enhanced the hypothesis that the enriched transcriptional regulators of the ARVC-related interactome have a key role in malignancy. The disorder where the input miRNAs were over-represented was esophageal cancer, followed by hepatocellular carcinoma and lung cancer. These findings are suggestive of potential significant associations between the predicted RNA molecules and cancer pathophysiology. The distinct sets of miRNAs for each enriched cancer type can be functionally validated in future research thus expanding our knowledge on the contribution of specific post-transcriptional regulators of ARVC-associated genes in carcinogenesis and tumor progression.