Role of metallothioneins in hepatocellular carcinoma

描述（由申请人提供）：长期目标是促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）是世界上第五大常见癌症，也是西半球癌症相关死亡的第三大原因。肝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，导致再生肝细胞转化。因此，通过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）是一种有效的抗氧化剂，可保护细胞免受活性氧的有害影响，而MT空细胞对产生自由基的外源药物敏感。肝脏富含MT-1和MT- 2这两种主要亚型。我们实验室和其他实验室的研究表明，MT在不同病因的原发性肝细胞癌中表达显著降低或消除。已知过表达MT的转基因小鼠表现出显著降低丙型肝炎病毒抗原诱导发病的严重程度。我们的假设是，MT的下调使肝细胞容易发生肿瘤转化，可能是肝癌发生的必要先决条件。本课题的具体目的是：(1)以MT敲除和MT过表达小鼠以及遗传匹配的对照动物为实验模型系统，阐明金属硫蛋白在化学（DEN/PB）诱导的肝癌（研究肝细胞癌的一个成熟的小鼠模型系统）中的作用；(2)研究PI3激酶靶点C/EBPa调控肝脏中MT基因表达的分子机制。希望本研究能够解决金属硫蛋白在肝癌发生的病因学中的作用，以及抑制其表达作为肝癌早期发现的诊断标志物。进一步，阐明其在肝癌发生过程中抑制的分子机制，至少可以揭示肝细胞恶性转化的一条重要途径。该方案也符合多个研究所的使命/目标，并与肝细胞癌病因学、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）上升的少数几种癌症之一。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肝癌早期检测的诊断标志物。进一步，阐明其抑制的分子机制，至少可以揭示肝细胞恶性转化的一条重要途径。该方案也符合多个研究所（NCI、NIDK、NIAA）的使命/目标，并与肝细胞癌病因学、预防和治疗的项目公告一致。

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.