NEGATIVE GROWTH REGULATORS IN NORMAL AND NEOPLASTIC LIVER

本项目的研究主要集中在：1)明确企业的角色 转化生长因子-β1在脑出血早期的表达 肝癌的发生，以及2)分离和鉴定 新型肝生长抑制药(LDGI)。我们使用了自发的 大鼠肝源性上皮细胞的转化 模型检验细胞生长抑制效应的变化 转化过程中转化生长因子-β1的表达。…的出现 形态异常的转化子与一种 种群对生长抑制的抵抗力增强 转化生长因子-β1的作用。克隆细胞系来源于 转化子对转化生长因子-β1依赖的抑制具有抗性。 DNA合成。这些细胞系也具有高度的致瘤性， 具有特征的粗大染色体异常的非整倍体，以及 表达了许多大鼠肝脏共有的表型标志物 癌基因或化学物质转化的上皮细胞。在……里面 相比之下，表面上看起来正常的细胞系是从同一个 种群无致瘤性，接近二倍体，染色体很少 大体异常，对转化生长因子-β1同样敏感 传代正常的RLE细胞。形态正常的晚期传代大鼠 肝上皮细胞对DNA转化敏感 去甲基化试剂5-氮杂-2-脱氧胞苷，与之前相反 传代细胞，这种转化伴随着 转化生长因子-1对生长抑制作用的抗性研究进展 Beta1。这些发现表明，获得对 生长抑制物如转化生长因子-β1的作用是一个重要的 而且可能是自然转变的关键阶段 RLE细胞。除了对转化生长因子-β1的研究外，我们目前正在进行 试图在高密度的数据库上获取部分蛋白质序列数据 LDGI的纯化部分。

The research in this project is focused on 1) defining the role of transforming growth factor-beta1 (TGF-beta1) in the early stages of hepatocarcinogenesis, and 2) isolation and characterization of a novel liver growth inhibitor (LDGI). We have used the spontaneous transformation of rat liver derived epithelial (RLE) cells as a model to examine the change in the growth inhibitory effects of TGF-beta1 during the transformation process. The appearance of morphologically aberrant transformants correlated directly with an increased resistance of the population to the growth inhibitory effects of TGF-beta1. Clonal cell lines derived from the transformants were resistant to TGF-beta1-dependent inhibition of DNA synthesis. These cell lines were also highly tumorigenic, aneuploid with characteristic gross chromosomal abnormalities, and expressed a number of phenotypic markers common to rat liver epithelial cells transformed by oncogenes or chemicals. In contrast, apparently normal-looking cell lines cloned from the same population were non-tumorigenic, near-diploid with few chromosomal gross abnormalities and were as sensitive to TGF-beta1 as early passage normal RLE cells. Morphologically normal late passage rat liver epithelial cells were sensitive to transformation by the DNA hypomethylating agent 5-aza-2-deoxycytidine, in contrast to earlier passage cells, and this transformation was accompanied by the development of resistance to the growth inhibitory effects of TGF- beta1. These findings suggest that acquisition of resistance to the effects of growth inhibitors such as TGF-beta1 is an important and possibly essential stage in the spontaneous transformation of RLE cells. In addition to the TGF-beta1 studies we are presently attempting to obtain partial protein sequence data on the highly purified fraction of LDGI.