How do persistent infections with hepatitis C virus cause liver cancer?

Abstract

Persistent infection with hepatitis C virus (HCV) is associated with an increased risk of hepatocellular carcinoma (HCC). Cancer typically develops in a setting of chronic hepatic inflammation and advanced fibrosis or cirrhosis, and such tissue represents a pre-neoplastic 'cancer field'. However, not all persistent infections progress to HCC and a combination of viral and host immune factors likely contributes to carcinogenesis. HCV may disrupt cellular pathways involved in detecting and responding to DNA damage, potentially adding to the risk of cancer. Efforts to unravel how HCV promotes HCC are hindered by lack of a robust small animal model, but a better understanding of molecular mechanisms could identify novel biomarkers for early detection and allow for development of improved therapies.

Figure 1. Organization of the 9.7 kb positive-sense HCV RNA genome

5’ and 3’ untranslated regions (UTRs) contain cis-acting elements essential for virus replication, including a 5’ internal ribosome entry site (IRES) that drives cap-independent expression of a polyprotein (box) that is processed into 10 mature viral proteins by a combination of host and viral proteases. Their functions are highlighted above the genome. The core (C) protein and envelope glycoproteins E1 and E2 are structural components of the virion. Nonstructural (NS) proteins possess functions necessary for replication, including helicase (NS3), protease (NS2 and NS3/4A), and RNA-dependent RNA polymerase (NS5B) activities. NS4B and NS5A drive formation of the ‘membranous web’, a cytoplasmic structure where these proteins accumulate to direct viral RNA synthesis. NS2 and NS5A also function in virion assembly, whereas p7 is essential for egress. Virus-host interactions that may contribute to HCC development are highlighted below the genome. Core and NS5A expression have been linked to the generation of ROS that may contribute to host DNA damage. Multiple HCV proteins interact with and modulate host pathways to facilitate virus replication and may in theory promote carcinogenesis.

Figure 2. Model for HCV-associated carcinogenesis

Hepatocellular carcinoma (HCC) likely results from a combination of indirect host- and direct HCV-mediated mechanisms. Persistent immune-mediated inflammation, coupled with expression of core and NS5A, generates ROS that trigger oxidative DNA damage. HCV infection further compromises host genome stability by impairing DNA repair pathways. Repeated cycles of hepatocellular destruction with regenerative proliferation and progressive fibrosis within this pro-mutagenic environment result in a “cancer field” comprised of pre-neoplastic but genetically-altered hepatocytes. Continued hepatocellular turnover may, in turn, select for aberrant hepatocytes with growth advantages. Whether HCC arises directly from HCV-infected hepatocytes remains unclear, although HCV infection may enhance survival of abnormal hepatocytes by promoting cell proliferation and inhibiting apoptosis. Ultimately, these combined mechanisms may select for transformed cells, culminating in development of HCC over 2-3 decades of persistent HCV infection.