Electronic Thesis/Dissertation


Inhibition of Hepatocyte Nuclear Factor 4α (HNF4α) in HCV Infection Promotes Hepatocarcinogenesis Open Access

Hepatocyte nuclear factor 4 alpha (HNF4α) plays critical role in liver development and hepatocyte function; transient suppression of HNF4α has been shown to initiate hepatocellular transformation (Hatziapostolou et al., 2011). Here we asked if sustained inhibition of HNF4αin hepatitis C virus (HCV) infected human primary hepatocytes promotes hepatocellular carcinoma (HCC). We present evidence that HCV-derived microRNA, vmr-11 inhibits HNF4α protein levels in HCV infected hepatocytes. Virus-derived 22nucleotide vmr-11 is sufficient to inhibit HNF4α, suggesting a direct role of HCV in the development of liver tumor. Sustained inhibition of HNF4α in mouse model of HCV-infection associated hepatocellular carcinoma (HCC) correlates with inhibition of E-Cadherin and the induction of Snail, and TGF-β expression, consistent with tumor suppressor function of HNF4α. Considering that HCV infection is an established cause of chronic hepatitis and hepatocellular carcinoma worldwide, our results showing viral non-coding RNA directed translational silencing of HNF4α tumor suppressor are consistent with a novel mechanism of HCV-infection induced HCC that should facilitate vmr-11-antagomir-based therapy for HCC.

Author Language Keyword Date created Type of Work Rights statement GW Unit Degree Advisor Committee Member(s) Persistent URL

Notice to Authors

If you are the author of this work and you have any questions about the information on this page, please use the Contact form to get in touch with us.