Genetic Alterations Promoting Alcohol Induced Hepatic Carcinogenesis

基因改变促进酒精诱发的肝癌发生

• 批准号: 8326615
• 负责人: Xin Chen
• 金额: $ 22.21万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2014-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8326615
• 关键词: Alcohol consumption; Alcoholic Liver Diseases; Alcohols; Animal Model; Biochemical; CCND1 gene; Cancer Etiology; Cessation of life; Chronic; Chronic Disease; Chronic Hepatitis C; Development; Disease model; Environment; Epigenetic Process; Event; Gene Expression; Gene Mutation; Genes; Genetic; Hepatic; Hepatitis; Hepatitis C; Hepatitis C virus; Hepatocarcinogenesis; Hepatocyte; Human; Incidence; Injection of therapeutic agent; Lead; Liver; Liver neoplasms; Malignant neoplasm of liver; Mediating; Methods; Modeling; Modification; Molecular; Molecular Genetics; Mus; Mutation; Oncogenes; Oncogenic; Pathogenesis; Pathway interactions; Patients; Prevention; Primary carcinoma of the liver cells; Risk Factors; Role; Sleeping Beauty; Testing; Therapeutic Intervention; Transgenic Mice; Tumor Tissue; Virus Diseases; c-myc Genes; cancer cell; carcinogenesis; feeding; flexibility; in vivo; innovation; innovative technologies; insight; meetings; mouse model; novel; overexpression; prevent; treatment strategy; tumor; tumor growth

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is one of the leading causes of cancer-related deaths worldwide. Chronic liver damage caused by chronic intake of alcohol and hepatitis viral infections is a major risk factor for HCC pathogenesis. In particular, there is compelling evidence that alcohol consumption and HCV infection synergistically induce liver damage, which culminates in an increased incidence of HCC. Molecular analyses and animal modeling have demonstrated that alcohol, with or without HCV infection, is not sufficient to induce HCC in vivo. It is believed that alcoholic liver disease (ALD), especially when accompanied by HCV infection, provides an environment that predisposes to HCC development. However, additional genetic mutations are required to transform the hepatocytes into malignant cells and induce liver tumor formation. In the present application, we hypothesize that certain genetic events, such as c-Myc or c-Met overexpression will lead to HCC formation in chronic alcohol fed mice and/or alcohol fed HCV Ns5a Transgenic (Ns5aTg) mice. In addition, we also hypothesize that chronic alcohol feeding will accelerate tumor growth induced by combination of oncogenes. To test these hypotheses, we propose the following two aims. In Aim One, we will determine whether c-Myc or c-Met overexpression leads to hepatic carcinogenesis in chronic alcohol fed wildtype mice or chronic alcohol fed HCV Ns5aTg mice. And in Aim Two, we will determine whether chronic alcohol feeding accelerates liver tumor growth induced by c-Met/CCND1 or c-Met/Spry2Y55F. Once we are able to establish HCC tumor models for ALD or ALD/HCV mice, we will further characterize the molecular, genetic and biochemical features as well as epigenetic modifications in the tumor tissues. Altogether, the proposed studies will assist to identify important driver oncogenes that have critical roles during liver cancer pathogenesis, and provide novel insight into the molecular mechanisms of HCC development in the context of alcohol induced liver injury. The novel mouse models established in the study will be of great usefulness to further characterize therapeutic interventions to prevent or treat hepatic carcinogenesis in patients with ALD.

描述（由申请人提供）：肝细胞癌（HCC）是全球癌症相关死亡的主要原因之一。慢性酒精摄入和肝炎病毒感染引起的慢性肝损伤是HCC发病的主要危险因素。特别是，有令人信服的证据表明，饮酒和HCV感染协同诱导肝损伤，最终导致HCC发病率增加。分子分析和动物模型表明，无论是否有HCV感染，酒精都不足以在体内诱导HCC。人们认为酒精性肝病（ALD），特别是伴随HCV感染时，提供了一个易发生HCC的环境。然而，需要额外的基因突变才能将肝细胞转化为恶性细胞并诱导肝肿瘤的形成。在目前的应用中，我们假设某些遗传事件，如c-Myc或c-Met过表达会导致慢性酒精喂养小鼠和/或酒精喂养HCV Ns5a转基因（Ns5aTg）小鼠的HCC形成。此外，我们还假设慢性酒精喂养会加速癌基因联合诱导的肿瘤生长。为了验证这些假设，我们提出了以下两个目标。在Aim 1中，我们将确定c-Myc或c-Met过表达是否会导致慢性酒精喂养野生型小鼠或慢性酒精喂养HCV Ns5aTg小鼠的肝癌发生。在第二阶段，我们将确定慢性酒精喂养是否会加速c-Met/CCND1或c-Met/Spry2Y55F诱导的肝脏肿瘤生长。一旦我们能够建立ALD或ALD/HCV小鼠的HCC肿瘤模型，我们将进一步表征肿瘤组织中的分子、遗传和生化特征以及表观遗传修饰。总之，这些研究将有助于确定在肝癌发病过程中起关键作用的重要驱动癌基因，并为酒精性肝损伤背景下HCC发展的分子机制提供新的见解。该研究建立的新型小鼠模型将对进一步表征治疗干预措施以预防或治疗ALD患者的肝癌发生具有重要意义。