Differential gene expression profiles in colon epithelium of two rat strains with distinct susceptibility to colon carcinogenesis after exposure to PhIP in combination with dietary high fat
Differential gene expression profiles in colon epithelium of two rat strains with distinct susceptibility to colon carcinogenesis after exposure to PhIP in combination with dietary high fat
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DOI：
10.1111/j.1349-7006.2003.tb01501.x
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发表时间：
2003-08-01
期刊：
影响因子：
5.7
通讯作者：
Nakagama, H
中科院分区：
文献类型：
--
作者：
Fujiwara, K;Ochiai, M;Nakagama, H
结肠癌是通过结肠上皮细胞的多种遗传和表观遗传改变的积累而发展的，而基因改变的上皮细胞的环境也可能对其进一步发展为癌症产生重大影响。本研究选取6周龄F344和ACl雄性大鼠，前者对2-氨基-1-甲基-6-苯基咪唑[4,5-b]吡啶（PhIP）诱导结肠癌易感，后者相对耐药，采用我们的PhIP间歇性喂养方案，结合高脂肪饮食进行长期致癌实验，PhIP是促进结肠癌发生的相关危险因素。60周处死动物，采用高密度寡核苷酸芯片对正常结肠上皮组织进行全局基因表达分析，以阐明F344和ACl菌株在正常结肠区域的差异基因表达谱（环境）。在RatU34A阵列的8799个条目中，有74个基因表现出3倍或更大的变异。编码核糖体rna和蛋白质的基因子集在F344菌株中高度优先表达。此外，编码脂肪酸结合蛋白和过氧化物酶体膜蛋白70的基因在易感菌株F344中出现上调。在ACl菌株中，错配修复基因Msh2与编码解毒酶儿茶酚- o -甲基转移酶的基因优先表达，其表达水平约为F344的20倍。正常结肠上皮组织中这些差异表达基因的综合作用可能解释了F344和ACl菌株对结肠癌的不同易感性。
Colon cancers develop through accumulation of multiple genetic and epigenetic alterations in colon epithelial cells, and the environment of the genetically altered epithelial cells may also have a substantial impact on their further development to cancer. In the present study, groups of 6-week-old F344 and ACl male rats, the former strain being susceptible to colon carcinogenesis induced by 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) and the latter being relatively resistant, were subjected to a long-term carcinogenesis experiment using our intermittent feeding protocol of PhIP in combination with a high-fat diet, which serves as a relevant risk factor that promotes the development of colon cancers. Animals were sacrificed at 60 weeks, and global gene expression analyses of normal parts of colon epithelial tissues were conducted using a high-density oligonucleotide microarray to elucidate the differential gene expression profile (environment) in normal colonic regions between F344 and ACl strains. Of 8799 entries on the RatU34A array, 74 genes exhibited 3-fold or greater variation. A subset of genes encoding ribosomal RNAs and proteins were highly preferentially expressed in the F344 strain. In addition, genes encoding fatty acid binding proteins and the peroxisome membrane protein 70 appeared up-regulated in the susceptible F344 strain. In the ACl strain, a mismatch repair gene, Msh2, was preferentially expressed, at approximately 20-fold the F344 level, along with a gene encoding a detoxification enzyme, catechol-O-methyltransferase. The combined effects of the repertoire of these differentially expressed genes in normal colon epithelial tissues may account for the distinct susceptibilities of F344 and ACl strains to colon carcinogenesis.