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。 在肝细胞癌的发生和预防中发挥重要作用。这个 用于这些拟议研究的模型是Long-Evans Cinnamon (LEC)大鼠，一种遗传性铜中毒大鼠的突变品种 自发地发展为肝细胞癌。MT，凭借这一多功能角色在 铜的代谢，它是金属的运输者、供体和 解毒剂，是了解糖尿病发病机制和预防的关键 这些动物体内的肝细胞癌。拟开展的研究主要集中在铜-MT代谢方面。 在LEC大鼠身上。铜-金属硫蛋白代谢的特定方面有待评估 包括它的诱导时间表，亚细胞分布 MT和铜，以及可能存在的铜-MT溶酶体代谢缺陷。 铜中毒活体治疗的疗效分析 LEC大鼠肝细胞癌的预防及其对肝细胞癌的影响 铜-线粒体的细胞代谢将有助于进一步确定MT在 细胞转化。其他研究将集中在潜在的 铜和MT代谢中的细胞缺陷导致 肝铜-MT在LEC肝细胞中的蓄积。这些研究是 由新开发的依赖温度的永生化细胞实现 来源于LEC和对照大鼠的细胞系。对其作用的进一步研究 肝细胞MT代谢中的溶酶体将通过开发实现 MT溶酶体进口体外检测方法的研究。 对这种独特的铜代谢异常模型的研究将有助于 阐明铜和金属硫蛋白在肝损伤过程中的作用 癌症发生，并提供信息，从哪些未来的治疗 可制定肝细胞癌的防治方案。

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.