Modulation of Cell Proliferation Pathways by the Hepatitis B Virus X Protein: A Potential Contributor to the Development of Hepatocellular Carcinoma

Globally, hepatocellular carcinoma (HCC) is the fifth most common cancer and the third highest cause of cancer-associated deaths. Although the development of HCC has been linked to exposure to various toxins or infectious agents, the majority of HCC cases are associated with chronic hepatitis B virus (HBV) infections [reviewed in (Block et al, 2003; Seeger et al, 2007)]. Worldwide, there are an estimated 350 million cases of chronic HBV infections, and approximately 25% of chronically HBV-infected individuals will eventually develop HCC [(Beasley et al, 1981); reviewed in (Seeger et al, 2007)]. The high global incidence of chronic HBV infections, high mortality rate of individuals with HCC, increased prevalence of HCC, and the close association between chronic HBV infections and HCC development have generated intense interest in understanding the molecular mechanisms that underlie the development of HBV-induced HCC. In this chapter, we provide a review of HBV biology and potential mechanisms that link a chronic HBV infection to the development of HCC. We specifically focus on activities of the HBV X protein (HBx), a multifunctional HBV protein that can alter hepatocyte physiology and stimulate HBV replication. While a brief survey of HBx activities that could influence HCC development is provided, we emphasize HBx regulation of intracellular calcium signaling and cell proliferation pathways as HBx activities that could potentially influence hepatocyte transformation.