GENETIC DETERMINANTS IN CHEMICAL HEPATOCARCINOGENESIS

化学性肝癌发生中的遗传决定因素

• 批准号: 3963542
• 负责人: S S THORGEIRSSON
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/3963542
• 关键词: Retroviridae; chemical carcinogen; chemical carcinogenesis; complementary DNA; genetic manipulation; liver cells; liver neoplasms; molecular oncology; oncogenes; viral carcinogenesis

The main objective of this project is to define the genetic determinants for the initiation stage in hepatocarcinogenesis and subsequent evolution of liver tumors that are brought about by chemical carcinogens and other cancer causing agents. The principal lesions that develop in the rat liver as a result of initiation-promotion protocols are foci of altered hepatocytes. Initiation of these foci by a variety of hepatocarcinogens has been shown to follow an apparent first order dose response, suggesting that the foci are a clonal expansion of the initiated cell. Consequently the phenotype of initiation should be completely represented by the foci of altered hepatocytes. To test this hypothesis we have started a series of experiments in which activated retroviral-associated oncogenes are transfected into a nontumorigenic rat liver epithelial cell line and primary rat hepatocytes, and the phenotypic changes determined. The research is currently focused on: (1) transfecting rat liver cells with retroviral associated oncogenes, (2) construction of a retroviral vector-based transfection system to introduce selected oncogenes into primary hepatocytes, and (3) construction of cDNA libraries from normal and neoplastic rat liver.

该项目的主要目标是确定遗传决定因素 用于肝癌发生的起始阶段和随后的演变 由化学致癌物和其他物质引起的肝脏肿瘤 致癌剂。 大鼠肝脏中发生的主要病变 由于启动促进协议是改变的焦点 肝细胞。 多种肝癌物质引发这些病灶 已被证明遵循明显的一级剂量反应，表明 焦点是起始细胞的克隆扩增。 最后 起始表型应完全由焦点来代表 改变的肝细胞。 为了检验这个假设，我们开始了一系列的研究 实验中激活的逆转录病毒相关癌基因 转染至非致瘤性大鼠肝上皮细胞系中并 原代大鼠肝细胞，并测定表型变化。 这 目前的研究主要集中在：（1）转染大鼠肝细胞 逆转录病毒相关癌基因，（2）逆转录病毒的构建 基于载体的转染系统，将选定的癌基因引入 原代肝细胞，以及（3）构建正常和正常肝细胞的cDNA文库 大鼠肝脏肿瘤。