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 including African Americans, Native Americans, and Asian Americans. Yet, the molecular mechanisms of carcinogenesis in chronic hepatitis B are unclear. In particular, it has not been convincingly shown in the literature that HBV itself is carcinogenic. Recent clinical data have pointed to an association between HCC and HBV mutants with in-frame deletions in the preS2 region of the surface gene that cause stress in the endoplasmic reticulum. We have generated transgenic mice containing a preS2 mutant HBV genome, and found that these mice develop HCC. This is the first direct demonstration of carcinogenesis induced by HBV in a transgenic mouse model using the entire HBV genome that is clinically relevant, and thus these mice represent the only model that is directly relevant to human HBV-associated HCC. We hypothesize that preS2 mutant HBV genomes play an important role in human HBV-associated carcinogenesis, by inducing stress in the endoplasmic reticulum, followed by oxidative stress, mitochondrial damage, and nuclear DMA damage. We will test this hypothesis with three specific aims. 1) We will characterize the neoplasms in these transgenic mice in terms of genomic instability, genetic loci with amplifications or deletions, and beta-catenin mutations, and compare the results with published data on human HCC caused by HBV. 2) We will determine if oxidative stress, mitochondrial damage, and nuclear DMA damage can be detected in our transgenic mice and in human livers infected with preS2 mutants; 3) We will determine if treatment of these mice with antioxidants will reduce the incidence of HCC. It is anticipated that these experiments will provide direct evidence on the role of preS2 mutants in HCC formation, begin to elucidate the molecular mechanisms of carcinogenesis during HBV infection, and lead in the future to the identification of molecular targets for the prevention and/or therapy of HCC. 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 causes more than 1.2 million deaths annually. Current treatment for hepatitis B is expensive and inadequate, and liver cancer has an extremely low cure rate. We hope that our research can lead to the development of new ways to prevent, detect, and/or treat liver cancer in these patients. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA055578-13
Application #
7391666
Study Section
Special Emphasis Panel (ZRG1-IDM-B (02))
Program Officer
Read-Connole, Elizabeth Lee
Project Start
1992-03-05
Project End
2012-01-31
Budget Start
2008-02-01
Budget End
2009-01-31
Support Year
13
Fiscal Year
2008
Total Cost
$245,449
Indirect Cost
Name
Northern California Institute Research & Education
Department
Type
DUNS #
613338789
City
San Francisco
State
CA
Country
United States
Zip Code
94121
Tang, Chi-Hui; Wei, Wei; Hanes, Martha A et al. (2013) Hepatocarcinogenesis driven by GSNOR deficiency is prevented by iNOS inhibition. Cancer Res 73:2897-904
Tang, Chi-Hui; Seeley, Eric J; Huang, Xiaozhu et al. (2013) Increased susceptibility to Klebsiella pneumonia and mortality in GSNOR-deficient mice. Biochem Biophys Res Commun 442:122-6
Wang, Qian; Na, Bing; Ou, Jing-hsiung James et al. (2012) Hepatitis B virus alters the antioxidant system in transgenic mice and sensitizes hepatocytes to Fas signaling. PLoS One 7:e36818
Tang, Chi-Hui; Wei, Wei; Liu, Limin (2012) Regulation of DNA repair by S-nitrosylation. Biochim Biophys Acta 1820:730-5
Ozawa, Kentaro; Tsumoto, Hiroki; Wei, Wei et al. (2012) Proteomic analysis of the role of S-nitrosoglutathione reductase in lipopolysaccharide-challenged mice. Proteomics 12:2024-35
Na, Bing; Huang, Zhiming; Wang, Qian et al. (2011) Transgenic expression of entire hepatitis B virus in mice induces hepatocarcinogenesis independent of chronic liver injury. PLoS One 6:e26240
Wei, Wei; Yang, Zhiyong; Tang, Chi-Hui et al. (2011) Targeted deletion of GSNOR in hepatocytes of mice causes nitrosative inactivation of O6-alkylguanine-DNA alkyltransferase and increased sensitivity to genotoxic diethylnitrosamine. Carcinogenesis 32:973-7
Zhou, Jie; Tan, Thomas; Tian, Yongjun et al. (2011) Kruppel-like factor 15 activates hepatitis B virus gene expression and replication. Hepatology 54:109-21
Sir, Donna; Tian, Yongjun; Chen, Wen-ling et al. (2010) The early autophagic pathway is activated by hepatitis B virus and required for viral DNA replication. Proc Natl Acad Sci U S A 107:4383-8
Zheng, Yanyan; Chen, Wen-ling; Louie, Stan G et al. (2007) Hepatitis B virus promotes hepatocarcinogenesis in transgenic mice. Hepatology 45:16-21

Showing the most recent 10 out of 23 publications