Hepatitis C virus core protein overcomes H2O2-induced apoptosis by downregulating p14 expression via DNA methylation

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 H 2 O 2 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 H 2 O 2 induced apoptotic cell death in p53-positive human hepatocytes, but not in p53-negative human hepatocytes. For this effect, H 2 O 2 upregulated levels of p14, increased ubiquitindependent 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 H 2 O 2 to activate the p14-MDM2-p53 pathway. As a consequence, HCV core-expressing cells could overcome p53-mediated apoptosis provoked by H 2 O 2 . Taken together, HCV core could contribute to hepatocellular carcinoma formation by removing deleterious roles of ROS inducing cell death.

Hepatitis C virus core or NS3/4A protein expression preconditions hepatocytes against oxidative stress and endoplasmic reticulum stress

“…H 2 O 2 treatment increased the levels of protein p14 and induced the ubiquitin-dependent degradation of mouse double minute 2 (MDM2) protein with a subsequent reduction of MDM2-p53 interaction, accumulation of p53 and activation of p53-dependent apoptotic pathways. In this model, HCV Core decreased p14 expression, resulting in inactivation of the p14-MDM2-p53 pathway [41].…”

“…There are only a few reports that investigated adaptive mechanisms of HCV-infected liver cells [21,41]. Seo et al, reported that HCV Core expressing HepG2 and Huh-7.5 cells are more resistant to hydrogen peroxide (H 2 O 2 )-induced toxicity.…”

Oxidative stress, a trigger of hepatitis C and B virus-induced liver carcinogenesis

“…It is noteworthy that both events involve reactive oxygen species as mediators. In addition, ROS suppress the expression of p14 protein that is implicated in induction of the proapoptotic p53-Mdm2 pathway [210]. Additional input into the survival of HCV-infected cells under chronic mitochondrial dysfunction comes from the induction of mitophagy, an event of autophagosomal removal of damaged mitochondria [211].…”

Mechanism of Hepatocyte Apoptosis

“…Several studies note that tumor suppressor p53 may be a target of the core. The proapoptotic effect of ROS is abolished when the p14–MDM2 (mouse double minute 2)-p53 pathway is repressed by the core through p14 promoter hypermethylation 70. Elevated sirt1 expression is another mechanism of p53 attenuation 71…”