Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide, and its incidence is rising in many countries. Like most types of cancer, hepatocarcinogenesis is a multistep process involving a number of different genetic alterations that ultimately lead to malignant transformation of the hepatocyte. Large geographic differences in the incidence of HCC suggest that environmental factors likely contribute to its development. However, the relative contribution of different factors and their molecular interactions are still poorly understood.

Epidemiological studies indicated that chronic viral infection is the most important oncogenetic agent for HCC development and hepatitis B (HBV)-associated carcinogenesis is currently construed as a multifactorial process comprising both direct and indirect mechanisms that likely act synergistically.1 In the Western world, 70–90% of HCC develop in a cirrhotic liver. Cirrhosis has been considered as a pre-neoplastic condition, as it leads to a hypermutagenic status that affects cell cycle genes and promotes deregulated proliferation.2 The strong association between cirrhosis and HCC suggests that the common pathway for hepatocarcinogenesis may be the increased liver cell turnover induced by chronic liver injury and regeneration, which induces or selects a malignant clone. However, while HBV-related HCC mostly develops in patients with underlying cirrhosis in the Caucasian population, the tumour occurs more frequently in the absence of cirrhosis in Asian patients. Thus, although it is clear that HBV-induced cirrhosis likely represents a major factor involved in liver carcinogenesis, evidence for a direct effect of HBV is rapidly growing.3

HBV-induced HCC probably results from a combination of different interacting effects; for example, the integration of HBV DNA and the transactivating activity of viral proteins, such as the enigmatic HBx and the truncated PreS2/S. Integration of HBV sequences into the host cell genome is not essential for viral replication, but it allows the viral genome to …