Viral non-coding RNA inhibits HNF4α expression in HCV associated hepatocellular carcinoma

Zhao Wang, Kristin Ceniccola, Liliana Florea, Bi Dar Wang, Norman H. Lee, Ajit Kumar

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article number19
JournalInfectious Agents and Cancer
Volume10
Issue number1
DOIs
StatePublished - Jul 8 2015

ASJC Scopus subject areas

  • Epidemiology
  • Oncology
  • Infectious Diseases
  • Cancer Research

Fingerprint Dive into the research topics of 'Viral non-coding RNA inhibits HNF4α expression in HCV associated hepatocellular carcinoma'. Together they form a unique fingerprint.

  • Cite this