Virus associated malignancies: the role of viral hepatitis in hepatocellular carcinoma

Abstract

Hepatocellular carcinoma (HCC) is the third leading fatal cancer worldwide and its incidence continues to increase. Chronic viral hepatitis involving either hepatitis B virus (HBV) or hepatitis C virus (HCV) infection is the leading etiology for HCC, making HCC prevention a major goal of antiviral therapy. While recent clinical observations and translational research have enhanced our understanding of the molecular mechanisms driving the initiation and progression of HCC, much remains unknown. Current data indicates that HCC tumors are highly complex and heterogeneous resulting from the aberrant function of multiple molecular pathways. This complex biology is responsible, at least in part, for the absence of highly efficient target-directed therapies for this deadly cancer. Additionally, the direct or indirect effect of HBV and HCV infection on the development of HCC is still a contentious issue. Thus, the question remains whether viral hepatitis-associated HCC stems from virus-specific factors, and/or from a general mechanism involving inflammation and tissue regeneration. In this review we summarize general mechanisms implicated in HCC, emphasizing data generated by new technologies available today. We also highlight specific pathways by which HBV and HCV could be involved in HCC pathogenesis. However, improvements to current in vitro and in vivo systems for both viruses will be needed to rigorously define the temporal sequence and specific pathway dysregulations that drive the strong clinical link between chronic hepatitis virus infection and HCC.

Keywords: Hepatitis B virus (HBV); Hepatitis C virus (HCV); Hepatocellular carcinoma (HCC); Oncogenesis; Viral hepatitis.

Fig 1. Gene structure and life cycle of HBV

A. An illustration of the small HBV genome with its unique overlapping gene structure. B. Life cycle of HBV. See text for details (Enh-Enhancer, Pol-polymerase, S-Surface).

Fig 2. General mechanisms for liver carcinogenesis and the role of viral factors in this process

Note that each mechanism implicated in liver carcinogenesis corresponds to the color of the putative viral factor triggering this mechanism.

Fig 3. The role of HCV gene products in liver carcinogenesis

(Upper) HCV is an RNA virus encoding for a polyprotein that is cleaved to individual structural (blue) and non-structural (green) proteins, essential for viral propagation and pathogenesis. (Lower) Putative mechanisms for carcinogenesis promoted by viral products (upwards arrows=up-regulation downwards arrows=down-regulation).