Hepatitis B virus (HBV) is a major cause of serious liver diseases, including chronic hepatitis, cirrhosis and hepatocellular carcinoma (HCC) throughout the world and the US, especially among minorities such as African Americans, Asian Americans, and Native Americans. Yet, the molecular mechanisms of carcinogenesis in chronic hepatitis B remain unsettled. Although it is clear that non-specific factors such as chronic inflammation and dietary carcinogens play important roles, there are no firm data on how HBV-specific factors may contribute to carcinogenesis. Recent clinical data have pointed to an association between HCC and HBV mutants with in-frame deletions and/or missense start codon mutation in the preS2 region of the surface gene. More importantly, we have generated transgenic mice containing a preS2 mutant HBV genome and shown that they develop HCC. These mice therefore constitute a novel and clinically relevant animal model of HBV-induced HCC. We propose two sets of experiments. 1) We will follow a cohort of these mice and study the histopathology of their livers at various time points, so that we can obtain a detailed understanding of the time course of HCC formation and the relationship to precursor lesions. 2) We will perform a molecular analysis of these liver tissues, to determine if ER stress and oxidative stress may be mechanistically involved in carcinogenesis. We will also relate the murine data to data we will obtain from human liver specimens. It is anticipated that these experiments will validate this unique mouse model and provide the groundwork for understanding the molecular basis of carcinogenesis in HBV-infected people, thereby pointing to future ways for designing novel preventive and therapeutic measures for this deadly disease. Hepatitis B virus is a major cause of suffering and death in the world, by causing liver injury, cirrhosis (liver scarring) and liver cancer. It is the second most deadly human virus, after human immunodeficiency virus, and causes more than 1.2 million deaths annually. Current treatment is expensive and inadequate, and we believe that our research will lead to the development of new ways to prevent, detect, or treat liver cancer in these patients. [unreadable] [unreadable] [unreadable]