CHOLINE DEFICIENCY AND HEPATOCARCINOGENESIS

本申请中提出的研究旨在研究 关于肝癌发生过程的几个方面。研究将会是 使用一个实验模型进行，不涉及使用 化学致癌物，诱导肝细胞的化学致癌物 只喂食不含胆碱的饮食的大鼠的癌症。在这个模型中， 肿瘤发生之前有一种异常的、慢性的 肝细胞的高增殖活性，并持续很长时间 这些动物成年后的生活。因此，似乎有可能，如果 不太可能，肿瘤的起源存在于 这种状态的长期性，或者出现新的变化(S 成人肝脏的分裂、生长和/或分化过程 细胞，在它的帮助下。慢性状态具有间歇性特征 与在成人肝脏再生中看到的类似，尖锐地， 在做了部分肝切除之后。在后者期间，一个瞬变 某些原癌基因表达增加。 将进行实验以调查喂食一只 大鼠无胆碱饮食可导致血管紧张素转换酶基因表达增加 肝细胞原癌基因(S)；这种增加，如果诱导， 只有在肝脏活跃增殖的情况下才能持续 细胞；以及肿瘤的发展是否可能与激活有关 原癌基因。 类似的研究也建议用化学药物治疗的大鼠进行。 致癌物，以探索后者的作用是否涉及 原癌基因表达改变(S)。最后，实验 建议，以确认和扩展初步发现，表明 出现一种以上的基因组改变可能是 化学致癌物诱发肝脏肿瘤所必需的。

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.