Role of S-nitroso-glutathione Reductase in Hepatocellular Carcinoma

S-亚硝基谷胱甘肽还原酶在肝细胞癌中的作用

• 批准号: 8193245
• 负责人: LIMIN LIU
• 金额: $ 27.99万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-08 至 2014-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8193245
• 关键词: Carcinogens; DNA Repair; DNA repair protein; Future; Genes; Genetic; Genetic Models; Genomics; Glutathione Reductase; Goals; Hepatocarcinogenesis; Hepatocyte; Human; Incidence; Incidence Study; Lead; Lesion; Liver; Malignant Neoplasms; Molecular; Mus; Nitric Oxide Synthase; O(6)-Methylguanine-DNA Methyltransferase; Patients; Prevalence; Prevention strategy; Primary carcinoma of the liver cells; Protein S; Risk; Role; Severities; System; Testing; United States; human NOS2A protein; in vivo; mortality; nitrosative stress; novel; novel strategies; overexpression; prevent; public health relevance; repaired; tumor; tumorigenesis

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.

描述（由申请人提供）：肝细胞癌（HCC）是全世界最常见和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。 HCC 主要病因的肝癌机制仍知之甚少。在 HCC 和许多易患 HCC 的病理状况中，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 合酶的合成水平上受到控制，而且还受到酶降解的控制，特别是 S-亚硝基谷胱甘肽还原酶 (GSNOR) 的降解。 GSNOR 控制体内蛋白质 S-亚硝基化的水平，对于防止 iNOS 衍生的亚硝化应激至关重要。人类 GSNOR 基因座位于 HCC 中最常缺失的染色体区域之一。我们培育了 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 对于预防肝脏肿瘤发生是否至关重要。具体目标是：1) 确定 GSNOR 对于预防小鼠肝细胞肿瘤发生是否至关重要； 2）阐明GSNOR在保护DNA修复系统中的作用和机制； 3) 检验 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 的病因机制提供新颖且根本性的贡献，并可能带来识别高危患者的新方法以及未来 HCC 的预防策略。 公共卫生相关性：肝细胞癌 (HCC) 是全世界最常见和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。我们期望我们的项目将为我们理解 HCC 的病因机制提供新颖且根本性的贡献，并可能带来识别高危患者的新方法以及未来 HCC 的预防策略。