GENETIC DETERMINANTS IN CHEMICAL HEPATOCARCINOGENESIS

化学性肝癌发生中的遗传决定因素

• 批准号: 3916835
• 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/3916835
• 关键词: Retroviridae; chemical carcinogen; chemical carcinogenesis; complementary DNA; drug resistance; epithelium; gene expression; genetic manipulation; laboratory rat; liver cells; liver neoplasms; messenger RNA; molecular oncology; neoplasm /cancer genetics; neoplastic transformation; oncogenes; preneoplastic state; tissue /cell culture; transforming growth factors; viral carcinogenesis

We have continued to utilize experimental hepatocarcinogenesis in the rat as a model to study the mechanism of neoplastic development with particular emphasis on defining the possible role of a set of oncogenes that are commonly associated with the process of hepatocarcinogenesis in vivo. Previous results had consistently shown up-regulation of the expression of myc and raf oncogenes during chemical hepatocarcinogenesis. In order to examine the transforming potential of these and other oncogenes in the liver system we have established an in vitro transformation system consisting of a retroviral vector containing relevant oncogenes and rat liver-derived epithelial (RLE) cell line as the reporter cell. The main findings include: (1) v-raf, H-v-ras and a combination of v-raf and v-myc are potent transforming agents in the RLE cells. (2) Different tumor types were observed following transplantation of the infected cells. The most undifferentiated tumors originated from the v-raf-infected cells whereas transformation with v-raf/f- myc combination resulted in hepatocellular carcinoma. (3) Transformation of RLE cells with v-raf and v-H-ras resulted in increased expression of the MDR-I gene and the development of multidrug resistance. (4) We have established that transforming growth factor-beta-1 (TGF-beta-1) is capable of differentiating the RLE cells towards the adult hepatocyte phenotype. Furthermore, transformation of the RLE cells block the TGF-beta induced differentiation of these cells.

我们继续利用实验性肝癌发生， 大鼠作为研究肿瘤发生机制的模型 并特别强调确定一套 癌基因通常与 体内肝癌发生。 以前的结果一直是 myc和raf癌基因表达上调 在化学性肝癌发生过程中。 为探讨 这些和其他癌基因在肝脏中的转化潜力 我们建立了一个体外转化系统 由含有相关致癌基因的逆转录病毒载体组成， 大鼠肝源性上皮（RLE）细胞系作为报告细胞。 主要结果包括：（1）v-raf、H-v-ras及两者的联合 v-raf和v-myc是RLE细胞中有效的转化剂。 (2)移植后观察不同的肿瘤类型 受感染的细胞。 大多数未分化肿瘤起源于 从V-raf感染的细胞中转化，而用V-raf/F- myc联合应用导致肝细胞癌。 （三） 用v-raf和v-H-ras转化RLE细胞， MDR-I基因表达增加， 多药耐药 (4)我们已经确定， 生长因子-β-1（TGF-β-1）能够分化成 RLE细胞向成体肝细胞表型转化。 此外，委员会认为， RLE细胞的转化阻断了TGF-β诱导的 这些细胞的分化。