Hepatitis B virus (HBV) is clearly associated with hepatocellular carcinomas, yet the mechanism of carcinogenesis is poorly understood. One possibility, strengthened by recent transgenic mouse studies, is that cellular necrosis and regeneration contribute significantly to carcinogenesis. In chronic HBV infection, there is appearance of so-called ground glass cells, which are cells with inspissated HBV surface proteins in the endoplasmic reticulum. Ground glass cells in transgenic mice can cause sufficient cellular damage and hepatic regeneration to induce hepatocellular carcinomas. Therefore, we would like to investigate how ground glass cells are produced in human infections. Our hypothesis is that genomic rearrangements of the HBV DNA, almost invariably present during chronic infection, cause dys-regulated transcription of the viral surface gene. This, in turn, leads to over synthesis of the large form of the surface protein, which is known to be capable of causing ground glass cells. We will test our hypothesis by generating mutant HBV clones, and looking for surface gene dys-regulation by transient transfections. We will further confirm that these mutations can cause ground glass cells in cultured cells and transgenic mice. It is hoped that these studies will lead to new insights on the pathogenesis of ground glass cells, and ultimately of hepatocellular carcinoma in HBV infection.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA055578-01
Application #
3200075
Study Section
Pathology B Study Section (PTHB)
Project Start
1992-03-05
Project End
1995-02-28
Budget Start
1992-03-05
Budget End
1993-02-28
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of California San Francisco
Department
Type
Schools of Medicine
DUNS #
073133571
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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