Chemopreventive n-3 polyunsaturated fatty acids reprogram genetic signatures during colon cancer initiation and progression in the rat
Chemopreventive n-3 polyunsaturated fatty acids reprogram genetic signatures during colon cancer initiation and progression in the rat
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DOI：
10.1158/0008-5472.can-04-1068
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发表时间：
2004-09-15
期刊：
影响因子：
11.2
通讯作者：
Chapkin, RS
中科院分区：
文献类型：
--
作者：
Davidson, LA;Nguyen, DV;Chapkin, RS
N-3多不饱和脂肪酸(PUFAs)降低结肠癌形成的机制尚未完全阐明。通过监测基因表达关系来检测在肿瘤发展的不同阶段上调或下调的基因，将有助于确定最终导致n-3PUFA保护作用的生物学过程。因此，采用3X2X2析因设计，我们使用包含类似9000个基因的Codelink DNA微阵列来帮助破译注射致癌物的SpragueDawley大鼠结肠细胞基因表达谱的全球变化。动物被分配到三个仅脂肪类型不同的饮食处理组(玉米油/n-6多不饱和脂肪酸、鱼油/n-3多不饱和脂肪酸或橄榄油/n-9单不饱和脂肪酸)、两个处理组(注射致癌物质偶氮甲烷或生理盐水)和两个时间点(第一次注射后12小时和10周)。只有n-3PUFA在起始阶段(DNA加合物形成)和促进阶段(异常隐窝病灶)起到保护作用。重要的是，对结肠细胞基因表达谱的微阵列分析发现，在12小时和10周的时间点上，n-3多不饱和脂肪酸治疗的动物之间存在根本差异。因此，除了证明在肿瘤发展的起始和促进阶段，膳食脂肪组成改变了结肠上皮基因表达谱的分子图谱外，这些发现还表明，鱼油的化学预防作用是由于n-3多不饱和脂肪酸的直接作用，而不是通过减少n-6多不饱和脂肪酸的含量。
The mechanisms by which n-3 polyunsaturated fatty acids (PUFAs) decrease colon tumor formation have not been fully elucidated. Examination of genes up- or down-regulated at various stages of tumor development via the monitoring of gene expression relationships will help to determine the biological processes ultimately responsible for the protective effects of n-3 PUFA. Therefore, using a 3 X 2 X 2 factorial design, we used Codelink DNA microarrays containing similar to9000 genes to help decipher the global changes in colonocyte gene expression profiles in carcinogen-injected Sprague Dawley rats. Animals were assigned to three dietary treatments differing only in the type of fat (corn oil/n-6 PUFA, fish oil/n-3 PUFA, or olive oil/n-9 monounsaturated fatty acid), two treatments (injection with the carcinogen azoxymethane or with saline), and two time points (12 hours and 10 weeks after first injection). Only the consumption of n-3 PUFA exerted a protective effect at the initiation (DNA adduct formation) and promotional (aberrant crypt foci) stages. Importantly, microarray analysis of colonocyte gene expression profiles discerned fundamental differences among animals treated with n-3 PUFA at both the 12 hours and 10-week time points. Thus, in addition to demonstrating that dietary fat composition alters the molecular portrait of gene expression profiles in the colonic epithelium at both the initiation and promotional stages of tumor development, these findings indicate that the chemopreventive effect of fish oil is due to the direct action of n-3 PUFA and not to a reduction in the content of n-6 PUFA.