Role of S-nitroso-glutathione Reductase in Hepatocellular Carcinoma

描述（由申请人提供）：肝细胞癌（HCC）是全球最常见和最致命的人类癌症之一，在美国，HCC的发病率和死亡率正在迅速增加。肝癌的主要致病因素的肝癌发生机制仍然知之甚少。在HCC和许多易患HCC的病理条件下，肝细胞通常高度表达诱导型一氧化氮合酶（iNOS），尽管NO在HCC中的作用尚不清楚。NO的生物活性不仅在NO合成水平上受到NO还原酶的控制，而且还受到酶促降解的控制，特别是受到S-亚硝基谷胱甘肽还原酶（GSNOR）的控制。GSNOR控制体内蛋白质S-亚硝基化的水平，并且对于保护免受iNOS衍生的亚硝化应激至关重要。人GSNOR基因座位于HCC中最常缺失的染色体区域之一。我们已经产生了GSNOR缺陷（GSNOR-/-）小鼠作为遗传模型来研究GSNOR在HCC中的作用。该项目的总体目标是确定GSNOR是否对防止肝脏肿瘤发生至关重要。具体目标是：1）确定GSNOR是否对小鼠肝细胞肿瘤发生具有重要的保护作用; 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HCC中经常缺乏的假设。我们期望该项目将为我们理解HCC的病因机制提供新的和根本性的贡献，并可能导致识别高危患者的新方法和未来HCC的预防策略。 公共卫生相关性：肝细胞癌（HCC）是世界范围内最常见和最致命的人类癌症之一，在美国，HCC的发病率和死亡率正在迅速增加。我们希望我们的项目将提供一个新的和根本性的贡献，我们的病因学机制的HCC的理解，并可能导致新的方法来识别患者的风险和未来的预防策略HCC。

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.