Elevated levels of STIM1, an endoplasmic reticulum Ca2+ sensor/buffering
protein, appear to be correlated with poor
cancer prognosis in which
microRNAs are also known to play critical roles. The purpose of this study is to investigate possible HBV origins of specific
microRNAs we identified in a stem cell-like subpopulation of Huh-7
hepatocellular carcinoma (HCC) cell lines with enhanced STIM1 and/or Orai1 expression that mimicked poor
cancer prognosis. Computational strategies including phylogenetic analyses were performed on miRNome data we obtained from an
EpCAM- and CD133-expressing Huh-7 HCC stem cell-like subpopulation with enhanced STIM1 and/or Orai1 expression originally cultured in the present work. Results revealed two putative regions in the HBV genome based on the apparent clustering pattern of stem loop sequences of
microRNAs, including miR3653. Reciprocal analysis of these regions identified critical human genes, of which their transcripts are among the predicted targets of miR3653, which was increased significantly by STIM1 or Orai1 enhancement. Briefly, this study provides phylogenetic evidence for a possible HBV-driven epigenetic remodeling that alters the expression pattern of Ca2+ homeostasis-associated genes in STIM1- or Orai1 overexpressing
liver cancer stem-like 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 viral genotype would have a clinical impact on prognosis of HBV-induced
liver cancers.