Implications of HBV-Driven Epigenetic Remodeling and Its Targets in Liver Cancer Stem Cells

Background: Elevated levels of STIM1, an endoplasmic reticulum Ca2+ sensor/buffering protein, appear to be correlated with poor cancer prognosis where microRNAs are also known to be involved. We investigated a possible viral origin of specific microRNAs identified in Huh-7 human liver cancer stem cells with enhanced STIM1 expression. Methods: Computational strategies including phylogenetic analyses were performed on miRNome data obtained from Huh-7 liver cancer stem cells with enhanced STIM1 and/or Orai1 expression originally cultured in the present study. Results: Results revealed two putative regions in HBV genome based on apparent clustering pattern of stem loop sequences of microRNAs, including miR3653. Reciprocal analysis of these regions revealed critical human genes of which their transcripts are among the predicted targets of miR3653 which was increased significantly by STIM1 enhancement. Conclusion: This study presents a phylogenetic evidence for an HBV-driven epigenetic remodeling to alter gene expression pattern associated with Ca2+ homeostasis in STIM1-overexpressing liver cancer stem cells for a possible mutual survival outcome. A novel region on HBV-X protein may affect liver carcinogenesis in a genotype-dependent manner. Therefore, detection of the HBV genotype would have a clinical impact on prognosis.