title: Viral non-coding RNA inhibits HNF4α expression in HCV associated hepatocellular carcinoma.
abstract: BACKGROUND
  Hepatitis C virus (HCV) infection is an established cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC); however, it is unclear if the virus plays a direct role in the development of HCC. Hepatocyte nuclear factor 4α (HNF4α) is critical determinant of epithelial architecture and hepatic development; depletion of HNF4α is correlated with oncogenic transformation. We explored the viral role in the inhibition of HNF4α expression, and consequent induction of tumor-promoting genes in HCV infection-associated HCC.
  
  
  METHODS
  Western blot analysis was used to monitor the changes in expression levels of oncogenic proteins in liver tissues from HCV-infected humanized mice. The mechanism of HNF4α depletion was studied in HCV-infected human hepatocyte cultures in vitro. Targeting of HNF4α expression by viral non-coding RNA was examined by inhibition of Luciferase HNF4α 3'-UTR reporter. Modulation of invasive properties of HCV-infected cells was examined by Matrigel cell migration assay.
  
  
  RESULTS
  Results show inhibition of HNF4α expression by targeting of HNF4α 3'-UTR by HCV-derived small non-coding RNA, vmr11. Vmr11 enhances the invasive properties of HCV-infected cells. Loss of HNF4α in HCV-infected liver tumors of humanized mice correlates with the induction of epithelial to mesenchymal transition (EMT) genes.
  
  
  CONCLUSIONS
  We show depletion of HNF4α in liver tumors of HCV-infected humanized mice by HCV derived small non-coding RNA (vmr11) and resultant induction of EMT genes, which are critical determinants of tumor progression. These results suggest a direct viral role in the development of hepatocellular carcinoma.
authors.affiliation: Department of Biochemistry, The George Washington University, Washington, DC USA.
authors.forename: Zhao
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, and Program in Molecular Oncology, The George Washington University, Washington, DC USA.
authors.forename: Kristin
authors.initials: K
authors.lastname: Ceniccola
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, The Johns Hopkins University, Baltimore, MD USA.
authors.forename: Liliana
authors.initials: L
authors.lastname: Florea
authors.affiliation: Department of Pharmacology, and Program in Molecular Oncology, The George Washington University, Washington, DC USA.
authors.forename: Bi-Dar
authors.initials: BD
authors.lastname: Wang
authors.affiliation: Department of Pharmacology, and Program in Molecular Oncology, The George Washington University, Washington, DC USA.
authors.forename: Norman H
authors.initials: NH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, The George Washington University, Washington, DC USA.
authors.forename: Ajit
authors.initials: A
authors.lastname: Kumar