Is hepatitis C virus carcinogenic?

Abstract

Although infection with hepatitis C virus (HCV) has become a leading cause of hepatocellular carcinoma, the mechanisms by which it results in carcinogenesis remain a subject of debate. Here, we explore the possibility that HCV replication impairs cellular DNA damage responses, thereby promoting instability of the infected host cell genome, and that HCV exerts a direct cancer-promoting effect in addition to eliciting immune-mediated inflammation and apoptosis of hepatocytes contributing to hepatocellular carcinogenesis.

Figure 1. Disruption of the Rb pathway by HCV NS5B

(A) Rb regulates multiple cellular processes, including cell cycle progression, apoptosis, DNA replication and repair, cellular differentiation and senescence. Rb binds to and represses E2F/DP transcription factor complexes. During the G1/S phase transition, Rb phosphorylation by cyclin-dependent kinases (CDKs) results in dissociation of Rb from E2F/DP complexes. The derepressed E2F/DP complexes are free to initiate transcription of S phase-specific genes, thus allowing cell cycle progression. (B) NS5B interacts with Rb in the cytoplasm of HCV-infected cells, and recruits the E3-ubiquitin ligase E6AP to facilitate ubiquitylation of Rb. (C) Ubiquitylation targets Rb for proteasome mediated degradation. Loss of Rb results in dysregulation of the many processes that Rb controls. For example, the unscheduled activation of E2F/DP-dependent gene expression can compromise cell cycle checkpoints that guard against chromosomal instability as well as induce p53-dependent apoptosis.

Figure 2. Direct versus indirect mechanisms of carcinogenesis in the HCV-infected liver

Competing scenarios depicting how liver cancer might arise within an infected cell as the direct result of viral protein expression (left), or in uninfected hepatocytes proliferating in response to the apoptotic death of infected cells (right). Direct vs. indirect mechanisms of carcinogenesis are not mutually exclusive and are subject to considerable overlap. The risk of cancer arising via either scenario is likely to be enhanced by the presence of cirrhosis, immune-mediated inflammation, and oxidative stress.