1887

Abstract

Infection with hepatitis C virus (HCV) is characterized by systemic oxidative stress that is caused by either viral core protein or chronic inflammation. It is well recognized that reactive oxygen species (ROS) such as HO can induce apoptotic cell death and can therefore function as anti-tumorigenic species. However, the detailed mechanisms by which ROS induce apoptotic cell death and HCV copes with the oxidative conditions are largely unknown. In the present study, we found that HO induced apoptotic cell death in p53-positive human hepatocytes, but not in p53-negative human hepatocytes. For this effect, HO upregulated levels of p14, increased ubiquitin-dependent degradation of mouse double minute 2 (MDM2), and reduced the interaction between MDM2 and p53 to prevent p53 degradation, resulting in accumulation of p53 and subsequent activation of p53-dependent apoptotic pathways. Interestingly, HCV core repressed p14 expression via promoter hypermethylation to abolish the potential of HO to activate the p14–MDM2–p53 pathway. As a consequence, HCV core-expressing cells could overcome p53-mediated apoptosis provoked by HO. Taken together, HCV core could contribute to hepatocellular carcinoma formation by removing deleterious roles of ROS inducing cell death.

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2015-04-01
2019-10-19
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