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

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

• Wang, Zhao

Language

• en

Keyword

• HCC
• HNF4&#945
• HCV
• EMT
• Hepatocyte

Date created

• 2013

Type of Work

• Master's Thesis

License

• All rights reserved

Rights statement

• In Copyright

GW Unit

• Biochemistry and Molecular Biology

Degree

• M.S.

Advisor

• Kumar, Ajit

Committee Member(s)

• Nair, Sujit S

Persistent URL

•  https://scholarspace.library.gwu.edu/etd/8w32r5641