GENETIC DETERMINANTS IN CHEMICAL HEPATOCARCINOGENESIS

我们继续利用实验性肝癌发生在 以大鼠为模型研究肿瘤发生机制 特别强调定义一组可能的角色 癌基因通常与肿瘤发生、发展过程有关 肝癌在体内的发生。之前的结果一直都是 Myc和raf癌基因表达上调 在化学性肝癌的发生过程中。为了检查 这些癌基因和其他癌基因在肝脏中的转化潜能 我们已经建立了一个体外转化系统 由含有相关癌基因的逆转录病毒载体和 以大鼠肝源性上皮(RLE)细胞系为报告细胞。 主要发现包括：(1)v-raf、H-v-ras及其组合 在RLE细胞中，v-raf和v-myc是有效的转移剂。 (2)移植后观察到不同的肿瘤类型。 被感染的细胞。最未分化的肿瘤起源于 从v-raf感染的细胞中获得，而用v-raf/f-... MYC联合导致肝细胞癌。(3) V-raf和v-H-ras对RLE细胞的转化 MDR-I基因表达增强与肿瘤的发生发展 多药耐药。(4)我们已经确定，转型 生长因子-β-1(TGF-β-1)能够分化为 RLE细胞向成体肝细胞表型转化。此外， RLE细胞转化阻断转化生长因子-β诱导 这些细胞的分化。

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.