Hepatitis C virus-induced activation of β-catenin promotes c-Myc expression and a cascade of pro-carcinogenetic events

Abstract

Chronic infection by hepatitis C virus (HCV) is a major risk factor for the onset and development of hepatocellular carcinoma (HCC), although the underlying mechanisms are unclear. The c-Myc oncogene contributes to the genesis of many types of cancers, including HCC, partly via the induction of genetic damage and the inhibition of the cellular response to genotoxic stress. Here, we show a previously undiscovered mechanistic link between HCV infection and enhanced c-Myc expression. c-Myc expression was augmented in non-tumoral liver tissues from HCV-infected individuals with or without HCC and in hepatocyte cell lines harboring an HCV replicon and the infectious HCV strain JFH1. Increased c-Myc expression was confirmed in vivo in a transgenic murine model expressing the entire HCV open reading frame, demonstrating a direct role for HCV protein expression in c-Myc induction. Mechanistically, activation of Akt by the HCV non-structural protein NS5A, and the subsequent stabilization of the transcription factor β-catenin, was demonstrated to be responsible for activation of the c-Myc promoter, and for increased c-Myc transcription. β-Catenin-dependent c-Myc expression in this context led to increased production of reactive oxygen species, mitochondrial perturbation, enhanced DNA damage and aberrant cell-cycle arrest. Together, these data provide a novel insight into the mechanisms involved in HCV-associated HCCs, strongly suggesting that c-Myc has a crucial contributory role in this process.

Alterations of Wnt/β-catenin signaling pathway in hepatocellular carcinomas associated with hepatitis C virus

“…Both ends of the NS5A protein (N and C) were found indispensable for the direct binding of β-catenin and for full activation of the protein within the Wnt pathway [8]. Recent studies of Higgs et al demonstrated a direct role for NS5A protein in β-catenin-dependent c-Myc expression [90].…”

Degrons in cancer

“…Furthermore, patients with liver cancer and underlying HCV infection exhibit a higher rate of mutation of b-catenin. Activation of AKT by the HCV nonstructural protein NS5A increased the transcriptional activity of b-catenin and also stabilized the protein through unknown mechanisms (269).…”

HCV infection, IFN response and the coding and non-coding host cell genome

“…Therefore, HCV infection could cause a MYC upregulation that increases PVT1 levels, which, in turn, increase the myc protein and lead to increased proliferation and hepatocarcinogenesis (Higgs et al, 2013).…”