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

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

doi:10.1186/s13027-015-0014-0

Abstract

BackgroundHepatitis 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.MethodsWestern 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.ResultsResults 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.ConclusionsWe 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.

Highlights

Hepatitis C virus (HCV) infection is an established cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC); it is unclear if the virus plays a direct role in the development of HCC
We examined the possible role of viral factors in the development of HCC using MUPuPA/SCID/Bg mice engrafted with human hepatocytes and infected with HCV [3]
Loss of Hepatocyte nuclear factor 4α (HNF4α) in HCV-infection associated hepatocellular carcinoma We attempted to establish a link between HCV infection and loss of HNF4α in HCV infection associated HCC using a recently reported [3] chimeric mouse model

Summary

Introduction

Hepatitis C virus (HCV) infection is an established cause of chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC); it is unclear if the virus plays a direct role in the development of HCC. We explored the viral role in the inhibition of HNF4α expression, and consequent induction of tumor-promoting genes in HCV infection-associated HCC. Hepatitis C virus (HCV) infection is a major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (HCC) [1]. Hepatocyte nuclear factor 4α (HNF4α) is member of the steroid hormone receptor superfamily of nuclear transcription factors with critical roles in hepatocyte differentiation, liver development and the maintenance of epithelial architecture [5, 6]. HNF4α plays a critical role in the maintenance of hepatic epithelium by suppressing expression of epithelial to mesenchymal transition (EMT)

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Results

Conclusion