Hepatitis B virus (HBV) is a major cause of hepatocellular carcinoma (HCC). However, how HBV may cause HCC remains controversial. It is unclear whether HBV can directly cause HCC or only indirectly cause HCC via the induction of chronic liver inflammation. The research on hepatocellular carcinogenesis induced by HBV has been difficult due to the narrow host range of this virus and the lack of a convenient animal model for its research. In recent years, transgenic mice carrying the entire HBV genome have been produced and used as a surrogate model for studying HBV replication and pathogenesis. These mice rarely develop hepatocellular neoplasia. However, in our preliminary studies, these mice were found to develop liver tumors at high frequencies if they were exposed once to the carcinogen diethylnitrosamine (DEN). In contrast, the control naive mice developed liver tumors at a very low frequency under the same experimental conditions. These preliminary studies indicate that HBV can directly promote hepatocellular oncogenesis initiated by carcinogens. The goal of this exploratory research application is to use this animal model to further understand the mechanisms of HBV-induced hepatocellular carcinogenesis. There are two specific aims.
The first aim i s to study how HBV interacts with DEN to induce liver tumors and to identify viral and host factors that may be involved in this oncogenic process. Male HBV carriers are more likely to develop HCC than female HBV carriers. Androgen and its receptor are believed to play an important role in this gender difference. Our preliminary studies indicate that the HBV X protein can enhance the gene transactivation activity of the androgen receptor (AR). Thus, the second aim of this application is to investigate whether the HBV X protein can enhance hepatocellular carcinogenesis mediated by AR. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Center for Research Resources (NCRR)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21RR021872-02
Application #
7296109
Study Section
Special Emphasis Panel (ZRG1-IDM-G (90))
Program Officer
O'Neill, Raymond R
Project Start
2006-09-17
Project End
2009-06-30
Budget Start
2007-07-01
Budget End
2009-06-30
Support Year
2
Fiscal Year
2007
Total Cost
$237,410
Indirect Cost
Name
University of Southern California
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
072933393
City
Los Angeles
State
CA
Country
United States
Zip Code
90089
Zheng, Yanyan; Chen, Wen-Ling; Ma, W-L Maverick et al. (2007) Enhancement of gene transactivation activity of androgen receptor by hepatitis B virus X protein. Virology 363:454-61