Liver cell transformation in chronic HBV infection

Abstract

Epidemiological studies have provided overwhelming evidence for a causal role of chronic HBV infection in the development of hepatocellular carcinoma (HCC), but the molecular mechanisms underlying virally-induced tumorigenesis remain largely debated. In the absence of a dominant oncogene encoded by the HBV genome, indirect roles have been proposed, including insertional activation of cellular oncogenes by HBV DNA integration, induction of genetic instability by viral integration or by the regulatory protein HBx, and long term effects of viral proteins in enhancing immune-mediated liver disease. In this chapter, we discuss different models of HBV-mediated liver cell transformation based on animal systems of hepadnavirus infection as well as functional studies in hepatocyte and hepatoma cell lines. These studies might help identifying the cellular effectors connecting HBV infection and liver cell transformation.

Keywords: HBx; hepatitis B virus; hepatocellular carcinoma; pathogenesis; transformation.

Figure 1.

Insertional activation of myc genes in WHV-induced woodchuck HCCs. The c-myc, N-myc1 and N-myc2 loci are represented as a line with exons as boxes and WHV insertion sites are shown with arrows. Under each locus are shown the preferred integration sites of retroviruses including murine leukemia virus (MLV), feline leukemia virus (FeLV), avian leukemia virus (ALV) and avian reticuloendotheliosis virus (REV). The b3n and win loci are located at 10 and 180 kb downstream of N-myc2 on the woodchuck X chromosome. Percentages of WHV integration at each locus in a panel of 70 woodchuck tumors analyzed are shown on the right side.

Figure 2.

Pleiotropic activities of the regulatory protein HBx. Here we depict a large array of HBx functions that may be relevant for cellular transformation, such as stimulation of virus replication, cell cycle deregulation, activation of signaling pathways, induction/repression of apoptosis and interference with DNA repair. Most of these functions are achieved through the transcriptional transactivation activity of HBx or by interactions with cellular partners in both cell cytoplasm and nucleus (shown as a grey ellipse).