DIETARY MODIFICATION & PROMOTION OF LIVER CARCINOGENESIS

这一更新补助金的总体目标是分析 在一个定义明确的模型中， 营养不良，并获得更好的了解 癌症发展的营养改变机制。 胆碱缺乏导致多种病理病变， 磷脂和乙酰胆碱合成减少， 不稳定甲基的供应。 a的共致癌作用 胆碱缺乏（CD）饮食对肝癌的诱导主要是 通过其促进行动进行调解，尽管关于 饮食本身的完全致癌性仍然存在。 几 改变CD饮食的促进功效的试剂具有 已确定，如脂肪的质量，降血脂剂， 美沙吡林、抗氧化剂和苯巴比妥。 CD饮食诱导 肝微粒体膜脂质过氧化损伤与 各种试剂修饰的脂质过氧化程度是 与肿瘤促进的疗效呈正相关， 苯巴比妥除外 我们假设其中一个 与肿瘤促进相关的关键细胞变化， 饮食引起的脂质过氧化可能是功能性的 细胞膜的改变。 我们最初的尝试表明 CD-肝细胞中的胰岛素受体发生了变化 和肝癌细胞，这可能是一种表现， 涉及细胞生长的细胞膜受体的改变 控制 我们建议在几个方向上扩展我们的研究， 评价i）多不饱和脂肪的影响具有高n-3脂肪酸 酸含量（鱼油）对CD促销的影响，ii） 报道的CD饮食诱导核脂质过氧化反应， 部分肝细胞，iii）饮食诱导的变化，在选定的 用于生长控制的膜受体（胰岛素、胰高血糖素、胰岛素 4. EGF和EGF受体的变化 肝肿瘤启动子的类型和v） 肿瘤前病变和肿瘤病变中的生长因子受体 在CD促销期间。 这些研究将提供关键的 关于饮食诱导的可能后果的信息 膜脂过氧化及其机制意义 与肝脏肿瘤促进有关。

The overall objective of this renewal grant is to analyze the process of liver carcinogenesis in a well defined model of nutritional deficiency and to gain a better understanding of the mechanisms of nutritional modifications of cancer development. Choline deficiency leads to a variety of pathological lesions due to a decrease in phospholipid and acetylcholine synthesis and in the supply of labile methyl groups. Co-carcinogenic effect of a choline deficient (CD) diet on liver cancer induction is primarily mediated through its promoting action, though the debates as to the complete carcinogenicity of the diet per se persist. Several agents which modify the promoting efficacy of a CD diet have been identified, such as the quality of fat, hypolipidemic agents, methapyrilene, antioxidant and phenobarbital. A CD diet induces peroxidative damage of liver microsomal membrane lipids and the extent of lipid peroxidation modified by various agents was positively correlated with the efficacy of tumor promotion with the exception of phenobarbital. We postulate that one of the critical cellular changes relevant to tumor promotion resulting from the diet-induced lipid peroxidation may be functional alterations of the cell membranes. Our initial attempt indicated that there were changes in insulin receptors in CD-hepatocytes and hepatoma cells which may be one manifestation of broader alterations of cell membrane receptors involving cell growth control. We propose to extend our studies in several directions by evaluating i) effects of polyunsaturated fat have a high n-3 fatty acid content (fish oil) on CD promotion, ii) possible significance of the reported CD diet induced lipid peroxidation in nuclear fraction of hepatocytes, iii) the diet induced changes in selected membrane receptors for growth control (insulin, glucagon, insulin like growth factors and EGF) iv) receptor changes by different types of liver tumor promoters and v) sequential changes of growth factor receptors in preneoplastic and neoplastic lesions during CD promotion. These studies will provide critical information regarding possible consequences of the diet-induced membrane lipid peroxidation and its mechanistic significance related to liver tumor promotion.