Role of metallothioneins in hepatocellular carcinoma

金属硫蛋白在肝细胞癌中的作用

• 批准号: 7257369
• 负责人: SAMSON T JACOB
• 金额: $ 18万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-04-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7257369
• 关键词: 1-Phosphatidylinositol 3-Kinase; Address; Alcohol abuse; Antioxidants; Binding; Biological Markers; Biological Models; Cancer Etiology; Candidate Disease Gene; Carcinogens; Cells; Cessation of life; Characteristics; Chemicals; Chronic; Cirrhosis; Control Animal; Cysteine; DNA Adduction; Diagnostic; Down-Regulation; Etiology; Event; Exhibits; Free Radicals; Frequencies; Gene Expression; Genes; Goals; Hepatic; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatocarcinogenesis; Hepatocyte; Hydroxyl Radical; Inflammation; Inflammatory; Injury; Institutes; Knock-out; Knockout Mice; Laboratories; Liver; Liver Cirrhosis; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Metallothionein; Metals; Mission; Modeling; Molecular; Mus; NIH Program Announcements; Natural regeneration; Neoplastic Cell Transformation; Nitrosamines; Null Lymphocytes; Numbers; Object Attachment; Oxidative Stress Induction; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Phenobarbital; Phosphoinositide-3-Kinase, Catalytic, Gamma Polypeptide; Play; Prevention; Primary carcinoma of the liver cells; Protein Isoforms; Protein Overexpression; Proteins; Reactive Nitrogen Species; Reactive Oxygen Species; Resistance; Role; SV40 T Antigens; Screening for Hepatocellular Cancer; Screening for cancer; Severities; Simian B disease; Singlet Oxygen; Testing; Trans-Activators; Transgenic Mice; United States; Viral Antigens; Wild Type Mouse; Xenobiotics; cancer type; mRNA Expression; macromolecule; men; mortality; mouse model; neoplastic; oxidation; promoter; tumor; tumorigenesis

DESCRIPTION (provided by applicant): The long term objective is to advance our understanding of the role of metallothionein in the etiology of certain types of cancer. Hepatocellular carcinoma (HCC) is the fifth most prevalent cancer in the world and is third leading cause of cancer related death in the Western hemisphere. A common characteristic of the liver carcinogens is induction of oxidative stress by inflammatory cells resulting in chronic hepatic injury that leads to transformation of regenerating hepatocytes. Scavenging of the reactive oxygen species (ROS) by antioxidants is, therefore, crucial for prevention of oxidative damage to cells that causes cancer. Metallothioneins (MT) are potent antioxidants that protect cells from deleterious effects of ROS whereas MT null cells are sensitive to xenobiotics that generate free radicals. Liver is abundant in both major isoforms of MT (MT-1 and MT- 2). Studies in our laboratory and other laboratories have shown that MT expression is dramatically reduced or abolished in primary hepatocellular carcinomas of different etiology. Transgenic mice overexpressing MT are known to exhibit significantly reduced severity of Hepatitis C viral antigen-induced pathogenesis. Our hypothesis is that down regulation of MT renders hepatocytes vulnerable to neoplastic transformation and may be an essential prerequisite for hepatocarcinogenesis. The specific aims of this proposal are to (1) Elucidate the role of metallothionein in chemical (DEN/PB)-induced hepatocarcinogenesis (a well established mouse model system to study hepatocellular carcinoma) using MT knockout and MT overexpressor mice along with genetically matched control animals as the experimental model system and (2) study the molecular mechanism by which C/EBPa, a target of PI3 kinase, regulates MT gene expression in the liver. It is hoped that this study will address the role of metallothionein in the etiology of hepatocarcinogenesis and suppression of its expression as a diagnostic marker for the early detection of liver cancer. Further, elucidation of the molecular mechanism of its suppression during hepatocarcinogenesis should reveal at least one of the important pathways in the malignant transformation of hepatocytes. This proposal also fits well with the mission/goals of multiple institutes and is consistent with the program announcement on etiology, prevention and treatment of hepatocellular carcinomas. Liver cancer results in nearly 15,000 deaths yearly and is one of the few cancers that is increasing in frequency and mortality (particularly in men) in the United States. The present study will address the role of metallothionein in the etiology of liver cancer and suppression of its expression as a diagnostic marker for the early detection of this cancer. Further, elucidation of the molecular mechanism of its suppression should reveal at least one of the important pathways in the malignant transformation of hepatocytes. This proposal also fits well with the mission/goals of multiple institutes (NCI, NIDK, NIAA) and is consistent with the program announcement on etiology, prevention and treatment of hepatocellular carcinomas.

描述（由申请人提供）：长期目标是增进我们对金属硫蛋白在某些类型癌症病因学中的作用的理解。肝细胞癌（HCC）是世界上第五大流行癌症，也是西半球癌症相关死亡的第三大原因。肝脏致癌物的一个共同特征是炎症细胞诱导氧化应激，导致慢性肝损伤，从而导致肝细胞再生转化。因此，抗氧化剂清除活性氧（ROS）对于预防导致癌症的细胞氧化损伤至关重要。金属硫蛋白 (MT) 是有效的抗氧化剂，可保护细胞免受 ROS 的有害影响，而 MT 无效细胞对产生自由基的异生物质敏感。肝脏富含 MT 的两种主要亚型（MT-1 和 MT-2）。我们实验室和其他实验室的研究表明，在不同病因的原发性肝细胞癌中，MT 表达显着减少或消失。已知过度表达 MT 的转基因小鼠表现出丙型肝炎病毒抗原诱导的发病机制的严重程度显着降低。我们的假设是，MT 的下调使肝细胞容易发生肿瘤转化，并且可能是肝癌发生的必要先决条件。该提案的具体目标是 (1) 使用 MT 敲除和 MT 过表达小鼠以及基因匹配对照阐明金属硫蛋白在化学 (DEN/PB) 诱导的肝癌发生中的作用（一个完善的研究肝细胞癌的小鼠模型系统） (2)研究PI3激酶靶标C/EBPa调节肝脏MT基因表达的分子机制。希望这项研究能够阐明金属硫蛋白在肝癌发生的病因学中的作用，并抑制其表达作为肝癌早期检测的诊断标志物。此外，阐明其在肝癌发生过程中抑制的分子机制应该揭示肝细胞恶性转化中的至少一个重要途径。该提案也非常契合多个机构的使命/目标，并且与肝细胞癌的病因学、预防和治疗的项目公告一致。肝癌每年导致近 15,000 人死亡，是美国发病率和死亡率（尤其是男性）不断增加的少数癌症之一。本研究将探讨金属硫蛋白在肝癌病因学中的作用，以及抑制其表达作为早期检测这种癌症的诊断标志物。此外，阐明其抑制的分子机制应该揭示肝细胞恶性转化中至少一个重要途径。该提案也非常符合多个机构（NCI、NIDK、NIAA）的使命/目标，并且与肝细胞癌的病因学、预防和治疗项目公告一致。