Role of S-nitroso-glutathione Reductase in Hepatocellular Carcinoma

描述（由申请人提供）：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，HCC的发病率和死亡率在美国迅速上升。HCC主要病因的致肝癌机制尚不清楚。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的生物活性不仅受NO合酶合成水平的控制，还受酶降解，特别是s -亚硝基谷胱甘肽还原酶（GSNOR）的控制。GSNOR控制体内蛋白质s -亚硝基化水平，对防止inos衍生的亚硝化应激至关重要。人类GSNOR位点位于HCC中最常缺失的染色体区域之一。我们用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。具体目的是：1)确定GSNOR是否对小鼠肝细胞肿瘤发生的保护至关重要；2)阐明GSNOR在DNA修复系统保护中的作用及机制；3)验证GSNOR在人类HCC中经常缺乏的假设。我们期望这个项目将为我们对HCC的病因机制的理解提供一个新的和基础的贡献，并可能导致新的方法来识别高危患者和未来的HCC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.