METALLOTHIONEIN AND LIVER CANCER IN THE LEC RAT

本研究的目的是确定金属硫蛋白（MT）的作用 肝细胞癌（HCC）的发展和预防。 的 用于这些拟议研究的模型是Long-Evans Cinnamon (LEC)大鼠，一种具有遗传性铜中毒的突变型大鼠， 自发地发展HCC。MT，凭借其多功能作用， 铜代谢，在那里它作为金属转运体，供体和 解毒剂，是了解发病机制和预防的关键 在这些动物中， 建议的研究重点是铜-MT代谢 在LEC大鼠中。 待评价的Cu-MT代谢的具体方面 包括其诱导的时间表， MT与铜的关系，以及铜-MT在溶酶体代谢中可能存在的缺陷。 铜中毒动物体内治疗的疗效分析 阻止LEC大鼠向HCC的进展及其对 铜-MT的细胞代谢将有助于进一步确定MT的作用， 细胞转化。 其他研究将集中在潜在的 铜和MT代谢的细胞缺陷导致 LEC肝细胞中肝铜MT的积累。 这些研究 通过新开发的温度依赖性永生化细胞 来源于LEC和对照大鼠的细胞系。 进一步研究《公约》 溶酶体在肝细胞MT代谢将实现发展 的体外测定的溶酶体输入MT。 研究这种独特的异常铜代谢模型将有助于 阐明铜和MT在肝硬化过程中的作用 致癌作用，并提供信息， 可以制定HCC的预防和治疗。

The goal of this study is to determine the role of metallothionein (MT) in the development and prevention of hepatocellular carcinoma (HCC). The model to be used for these proposed studies is the Long-Evans Cinnamon (LEC) rat, a mutant breed of rats wit inherited copper toxicosis which spontaneously develop HCC. MT, by virtue of this multifunctional role in copper metabolism where it serves as a metal transporter, donor and detoxifier, is key to understanding the pathogenesis and prevention of HCC in these animals. The proposed studies focus on copper-MT metabolism in the LEC rat. Specific aspects of Cu-MT metabolism to be evaluated include the timetable for its induction, the subcellular distribution of MT and copper, and the possible defect in lysosomal metabolism of Cu-MT. Analysis of the efficacy of in-vivo treatment of copper toxicosis for preventing the progression to HCC in LEC rats and its effect on the cellular metabolism of copper-Mt will help further define MT's role in cellular trans-formation. Other studies will focus on the underlying cellular defect in copper and MT metabolism which leads to the accumulation of hepatic copper-MT in LEC hepatocytes. These studies are made possible by newly developed temperature dependent immortalized cell lines derived from LEC and control rats. Further study of the role of lysosomes in hepatocellular MT metabolism will be achieved by development of in-vitro assays for the lysosomal import of MT. Study of this unique model of aberrant copper metabolism will help elucidate the role of copper and MT in the process of hepatic carcinogenesis, and provide information from which future therapies for the prevention and treatment of HCC may be formulated.