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.

Abstract

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 ACI 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 ACI 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 ACI 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 ACI strains to colon carcinogenesis.