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

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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.

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