CHOLINE DEFICIENCY AND HEPATOCARCINOGENESIS

本申请中提出的研究旨在研究 肝癌发生过程的各个方面。 研究将 用一个实验模型进行，不涉及使用 化学致癌物，诱导肝细胞 只喂食无胆碱饮食的大鼠的癌症。 在这个模型中， 肿瘤发展之前是异常的慢性状态， 肝细胞的高增殖活性，持续很长时间 成年动物的生活。 因此，如果 不太可能，肿瘤的起源存在于 这种状态的长期性，或在这种状态中出现的新变化， 成人肝脏的分裂、生长和/或分化过程 细胞，由它促进。慢性状态具有发作性特征 类似于在成人肝再生中急性观察到的， 部分肝切除术后死亡 在后一种情况下， 某些原癌基因表达的增加。 将进行实验以研究是否喂食 缺乏胆碱的饮食给大鼠， 肝细胞原癌基因;如果诱导， 只有在肝脏活跃增生时才会持续 细胞;以及肿瘤的发展是否可能与激活有关 原癌基因 类似的研究建议使用化学治疗的大鼠 致癌物质，探讨后者的作用是否涉及 原癌基因表达的改变。 最后，实验 提出，以确认和扩展初步调查结果，表明 多于一个基因组改变的发生可能 化学致癌物诱导肝肿瘤所需的。

The research proposed in this application is designed to study aspects of the process of hepatocarcinogenesis. Studies will be carried out with one experimental model not involving the use of chemical carcinogens, that of induction of hepatocellular carcinomas in rats solely fed a choline-devoid diet. In this model, tumor development is preceded by an abnormal, chronic state of high proliferative activity of liver cells, which persists for much of the adult life of the animals. It seems possible therefore, if not likely, that the genesis of the tumors resides in either the chronicity of such a state, or new alteration(s) arising in the processes of division, growth and/or differentiation of adult liver cells, facilitated by it. The chronic state has episodic features similar to those seen, acutely, in the adult liver regeneration that follows a partial hepatectomy. During the latter, a transient increase in the expression of certain proto-oncogenes. Experiments will be performed to investigate whether feeding a choline-devoid diet to rats results in an increased expression of liver cell proto-oncogene(s); whether such an increase, if induced, persists only for as long as there is an active proliferation of liver cells; and whether tumor development may be linked to activation of proto-oncogenes. Similar studies are proposed using rats treated with chemical carcinogens, to explore whether the action of the latter involve alteration(s) in proto-oncogene expression. Finally, experiments are proposed, to confirm and extend initial findings indicating that occurrence of more than one genomic alteration may be required for induction of liver tumors by chemical carcinogens.