Hepatocellular carcinoma (HCC) is one of the most common and deadly human cancers worldwide, and incidence and mortality for HCC is increasing rapidly in the United States. Hepatocarcinogenic mechanisms of major etiologic factors of HCC remain poorly understood. In both HCC and many pathological conditions that predispose to HCC, liver cells often highly express the inducible nitric oxide synthase (iNOS), although the role of NO in HCC is unknown. NO bioactivity is controlled not only at the level of synthesis by NO synthases, but also by enzymatic degradation, in particular by S-nitroso-glutathione reductase (GSNOR). GSNOR controls the level of protein S-nitrosylation in vivo, and is critically important for protection against iNOS-derived nitrosative stress. Human GSNOR locus is located in one of the most frequently deleted chromosomal regions in HCC. We have generated GSNOR-deficient (GSNOR-/-) mice as a genetic model to study the role of GSNOR in HCC. The overall goal of this project is to determine if GSNOR is critically important for protection against liver tumorigenesis.
The specific aims are: 1) to determine whether GSNOR is critically important for protection against hepatocellular tumorigenesis in mice;2) to elucidate the role and mechanism of GSNOR in protection of DNA repair system;3) to test the hypothesis that GSNOR is frequently deficient in human HCC. We expect that this project will provide a novel and fundamental contribution to our understanding of the etiologic mechanism of HCC, and might lead to novel approaches for identifying patients at risk and to future preventive strategies for HCC.

Public Health Relevance

Hepatocellular carcinoma (HCC) is one of the most common and deadly human cancers worldwide, and incidence and mortality for HCC is increasing rapidly in the United States. We expect that our project will provide a novel and fundamental contribution to our understanding of the etiologic mechanism of HCC, and might lead to novel approaches for identifying patients at risk and to future preventive strategies for HCC.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA122359-04
Application #
8256594
Study Section
Cancer Etiology Study Section (CE)
Program Officer
Johnson, Ronald L
Project Start
2009-05-08
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2013-04-30
Support Year
4
Fiscal Year
2012
Total Cost
$279,874
Indirect Cost
$98,726
Name
University of California San Francisco
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
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Leung, James; Wei, Wei; Liu, Limin (2013) S-nitrosoglutathione reductase deficiency increases mutagenesis from alkylation in mouse liver. Carcinogenesis 34:984-9
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
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
Khan, Omar; Headley, Mark; Gerard, Audrey et al. (2011) Regulation of T cell priming by lymphoid stroma. PLoS One 6:e26138
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
Yang, Zhiyong; Wang, Zhi-En; Doulias, Paschalis-Thomas et al. (2010) Lymphocyte development requires S-nitrosoglutathione reductase. J Immunol 185:6664-9