Methyl groups in carcinogenesis: effects on DNA methylation and gene expression.
Methyl groups in carcinogenesis: effects on DNA methylation and gene expression.
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发表时间：
1992-04
期刊：
影响因子：
11.2
通讯作者：
E. Wainfan;L. Poirier
中科院分区：
文献类型：
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作者：
E. Wainfan;L. Poirier
缺乏促脂蛋白（甲基缺乏）的饮食会导致脂肪肝和肝细胞更新增加，并促进啮齿动物的致癌作用。在大鼠中，长期摄入甲基缺乏的饮食导致肝肿瘤的发展。这种缺陷的促癌和致癌特性的机制尚不清楚。这里描述的实验结果支持这样的假设，即摄入这样的饮食，通过引起S-腺苷甲硫氨酸池的消耗，导致DNA低甲基化，这反过来又导致可能在生长调节中起关键作用的基因表达的变化。在喂食严重甲基缺乏饮食（MDD）的大鼠肝脏中，在1周内观察到S-腺苷甲硫氨酸和低甲基化DNA的池降低。MDD喂养时间越长，DNA低甲基化程度越高。DNA甲基化总体水平的降低伴随着基因表达的同时改变，产生的模式与报道的暴露于促癌化学物质的动物肝脏和肝癌中发生的模式非常相似。从喂食对照或缺乏饮食的大鼠肝脏中提取的多聚腺苷酸化RNA的北方印迹分析表明，在摄入MDD 1周后，c-myc和c-fos癌基因的mRNA水平大幅增加，c-Ha-ras mRNA水平略有增加，而c-Ki-ras mRNA水平几乎没有变化。与此相反，表皮生长因子受体的mRNA显着下降。c-myc、c-fos和c-Ha-ras基因表达水平的升高伴随着指定这些基因的序列内甲基化模式的选择性变化。MDD喂养1个月的大鼠肝脏中诱导的DNA甲基化和基因表达的变化在恢复足够的饮食后逐渐逆转。在长期膳食甲基缺乏引起的肝癌中，c-Ki-ras和c-Ha-ras的甲基化模式异常。虽然人类饮食不太可能像这些实验中使用的那样严重缺乏甲基，但在世界某些地区，摄入蛋氨酸和胆碱含量低并被黄曲霉毒素等真菌毒素污染的饮食是常见的。即使在工业化国家，缺乏叶酸和维生素B12也并不罕见，某些治疗剂和药物滥用会加剧这种情况。因此，饮食和污染物或药物的相互作用，通过诱导DNA甲基化和异常基因表达的变化，可能有助于人类癌症的病因。
Lipotrope-deficient (methyl-deficient) diets cause fatty livers and increased liver-cell turnover and promote carcinogenesis in rodents. In rats prolonged intake of methyl-deficient diets results in liver tumor development. The mechanisms responsible for the cancer-promoting and carcinogenic properties of this deficiency remain unclear. The results of the experiments described here lend support to the hypothesis that intake of such a diet, by causing depletion of S-adenosylmethionine pools, results in DNA hypomethylation, which in turn leads to changes in expression of genes that may have key roles in regulation of growth. In livers of rats fed a severely methyl-deficient diet (MDD), lowered pools of S-adenosylmethionine and hypomethylated DNA were observed within 1 week. The extent of DNA hypomethylation increased when MDD was fed for longer periods. The decreases in overall levels of DNA methylation were accompanied by simultaneous alterations in gene expression, yielding patterns that closely resembled those reported to occur in livers of animals exposed to cancer-promoting chemicals and in hepatomas. Northern blot analysis of polyadenylated RNAs from livers of rats fed control or deficient diets showed that, after 1 week of MDD intake, there were large increases in levels of mRNAs for the c-myc and c-fos oncogenes, somewhat smaller increases in c-Ha-ras mRNA, and virtually no change in levels of c-Ki-ras mRNA. In contrast, mRNAs for epidermal growth factor receptor decreased significantly. The elevated levels of expression of the c-myc, c-fos, and c-Ha-ras genes were accompanied by selective changes in patterns of methylation within the sequences specifying these genes. Changes in DNA methylation and in gene expression induced in livers of rats fed MDD for 1 month were gradually reversed after restoration of an adequate diet. In hepatomas induced by prolonged dietary methyl deficiency, methylation patterns of c-Ki-ras and c-Ha-ras were abnormal. Although human diets are unlikely to be as severely methyl deficient as those used in these experiments, in some parts of the world intake of diets that are low in methionine and choline and contaminated with mycotoxins, such as aflatoxin, are common. Even in industrialized nations, deficiencies of folic acid and vitamin B12 are not uncommon and are exacerbated by some therapeutic agents and by substance abuse. Thus, it seems possible that interactions of diet and contaminants or drugs, by inducing changes in DNA methylation and aberrant gene expression, may contribute to cancer causation in humans.