Oxidative Stress and Hepatocellular Carcinoma

氧化应激与肝细胞癌

• 批准号: 7892272
• 负责人: Ting-Ting Huang
• 金额: $ 26.6万
• 依托单位: PALO ALTO VETERANS INSTIT FOR RESEARCH
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-21 至 2012-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7892272
• 关键词: Accounting; Adult; Affect; Animals; Antioxidants; Biological Markers; Calcium; Cell Line; Cells; China; Chronic; Cirrhosis; Clinical Research; Country; Development; Genes; Genetic; Goals; Hand; Hemochromatosis; Hepatitis B; Hepatitis B Virus; Hepatitis C; Hepatocarcinogenesis; Hepatocyte; Homeostasis; Human; In Vitro; Infection; Injury; Investigation; Italy; Japan; Left; Life; Liver; Liver diseases; Liver neoplasms; Long-Term Effects; Longitudinal Studies; Malignant Neoplasms; Malignant neoplasm of liver; Mediating; Metabolism; Modeling; Modification; Molecular; Molecular Target; Mus; Mutant Strains Mice; Mutation; Operative Surgical Procedures; Oxidation-Reduction; Oxidative Stress; Patients; Play; Primary carcinoma of the liver cells; Probability; Procedures; Production; Protein C Inhibitor; Proteins; Proteomics; Risk Factors; Role; Signaling Molecule; Superoxide Dismutase; Surveys; System; Taiwan; Time; Transgenic Mice; Transgenic Organisms; Treatment outcome; Tumor Tissue; United States; base; biological adaptation to stress; citrate carrier; comparative; congenic; copper zinc superoxide dismutase; driving force; free radical oxygen; in vivo; mouse model; mutant; non-alcoholic fatty liver; nonalcoholic steatohepatitis; oxidation; oxidative damage; problem drinker; tool; transcription factor

DESCRIPTION (provided by applicant): This proposal is based on the hypothesis that oxidative stress and injury is a common and major driving force of hepatocellular carcinoma (HCC) in chronic liver diseases and that decreased antioxidant capacity increases the probability of HCC development in patients with chronic liver diseases. Therefore, the long term objectives of this proposal are to determine the mechanism underling oxidative stress-mediated HCC development from hepatitis C (HCV) infection and to identify risk factors and oxidative stress-mediated biomarkers associated with the progression of HCC. Several clinical studies showed a causal relationship between low levels of superoxide dismutase (SOD) and the development of HCC; several mouse models generated to recapitulate HCC development were shown to have elevated levels of oxidative damage; and mutant mice with genetic defects in oxygen free radical metabolism develop HCC after a long incubation time. Collectively, these studies suggest that oxidative stress may play a direct and important role in the development of HCC in chronic liver diseases. We will focus our studies on the interplay between HCV-mediated HCC development, oxidative stress, and SOD deficiency in this proposal. Three Specific Aims are proposed to determine the relationship between HCV infection, ROS production, calcium homeostasis, and hepatocarcinogenesis, to determine the role of SOD in the development of HCV-mediated hepatocarcinogenesis, and to identify molecular targets common to chronic HCV infection and SOD deficiency by comparative proteomic analyses. In vitro and in vivo studies using established human liver cell line, primary human hepatocytes, HCV transgenic mice, and CuZnSOD deficient mice will be carried out to determine the effects of HCV proteins on ROS production, calcium homeostasis, and the activation of redox-sensitive signaling molecules. A genetic approach will be used to reduce SOD levels in HCV transgenic mice to modulate the course of HCC development. In addition, different proteomic tools and procedures will be implemented to identify molecules that are vulnerable to oxidative modification in HCV transgenic and CuZnSOD deficient mice.

描述（由申请人提供）：该提案基于以下假设：氧化应激和损伤是慢性肝病中肝细胞癌（HCC）的常见且主要驱动力，并且抗氧化能力下降会增加慢性肝病患者发生HCC的可能性。因此，该提案的长期目标是确定丙型肝炎（HCV）感染导致氧化应激介导的 HCC 发展的机制，并确定与 HCC 进展相关的危险因素和氧化应激介导的生物标志物。多项临床研究表明，低水平的超氧化物歧化酶 (SOD) 与 HCC 的发展之间存在因果关系。一些用于重现 HCC 发展的小鼠模型被证明氧化损伤水平升高；具有氧自由基代谢遗传缺陷的突变小鼠在长时间潜伏后会发展为肝癌。总的来说，这些研究表明氧化应激可能在慢性肝病 HCC 的发展中发挥直接而重要的作用。在本提案中，我们将重点研究 HCV 介导的 HCC 发展、氧化应激和 SOD 缺乏之间的相互作用。提出了三个具体目标，以确定 HCV 感染、ROS 产生、钙稳态和肝癌发生之间的关系，确定 SOD 在 HCV 介导的肝癌发生发展中的作用，并通过比较蛋白质组学分析确定慢性 HCV 感染和 SOD 缺乏的常见分子靶点。将使用已建立的人肝细胞系、原代人肝细胞、HCV转基因小鼠和CuZnSOD缺陷小鼠进行体外和体内研究，以确定HCV蛋白对ROS产生、钙稳态和氧化还原敏感信号分子激活的影响。遗传方法将用于降低 HCV 转基因小鼠的 SOD 水平，以调节 HCC 的发展过程。此外，将采用不同的蛋白质组学工具和程序来鉴定 HCV 转基因和 CuZnSOD 缺陷小鼠中易受氧化修饰的分子。