Role of S-nitroso-glutathione Reductase in Hepatocellular Carcinoma

描述(申请人提供)：肝细胞癌是世界范围内最常见和最致命的人类癌症之一，在美国，肝癌的发病率和死亡率正在迅速上升。肝细胞癌的主要致病因素的致癌机制尚不清楚。在肝细胞癌和许多易患肝细胞癌的病理条件下，肝细胞通常高表达诱导型一氧化氮合酶(INOS)，尽管NO在肝细胞癌中的作用尚不清楚。NO的生物活性不仅受一氧化氮合酶控制，还受酶的降解控制，特别是受S亚硝基谷胱甘肽还原酶的控制。GSNOR控制体内S亚硝化蛋白的水平，对于保护诱导型一氧化氮合酶亚硝化应激至关重要。人类GSNOR基因座位于肝细胞癌最常见的缺失染色体区域之一。我们已经建立了GSNOR缺陷(GSNOR-/-)小鼠作为遗传模型来研究GSNOR在肝细胞癌中的作用。该项目的总体目标是确定GSNOR对于防止肝脏肿瘤发生是否至关重要。其具体目的是：1)确定GSNOR是否对小鼠肝细胞肿瘤的发生具有至关重要的保护作用；2)阐明GSNOR在保护DNA修复系统中的作用和机制；3)验证GSNOR在人类肝癌中经常缺失的假设。我们期望这个项目将为我们理解肝细胞癌的病因机制提供一个新的和基本的贡献，并可能导致识别高危患者的新方法和未来的肝细胞癌预防策略。 公共卫生相关性：肝细胞癌是世界范围内最常见和最致命的人类癌症之一，在美国，肝癌的发病率和死亡率正在迅速上升。我们期待我们的项目将为我们理解肝细胞癌的病因机制提供一个新的和基本的贡献，并可能导致识别高危患者的新方法和未来的肝细胞癌预防策略。

DESCRIPTION (provided by applicant): 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.