Colon cancers develop after accumulation of multiple genetic and epigenetic alterations in colon epithelial cells. To shed light on global changes in gene expression of colon cancers and to gain further insight into the molecular mechanisms underlying colon carcinogenesis, we have conducted a comprehensive microarray analysis of mRNA using a rat colon cancer model with the food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP). Of 8749 genes or ESTs on a high density oligonucleotide microarray, 27 and 46 were over- and underexpressed, respectively, by > or =3-fold in colon cancers in common in two rat strains with distinct susceptibility to PhIP carcinogenesis. For example, genes involved in inflammation and matrix proteases and a cell cycle regulator gene, cyclin D2, were highly expressed in colon cancers. In contrast, genes encoding structural proteins, muscle-related proteins, matrix-composing and mucin-like proteins were underexpressed. Interestingly, a subset of genes whose expression is characteristic of Paneth cells, i.e. the defensins and matrilysin, were highly overexpressed in colon cancers. The presence of defensin 3 and defensin 5 transcripts in cancer cells could also be confirmed by in situ mRNA hybridization. Furthermore, Alcian blue/periodic acid Schiff base (AB-PAS) staining and immunohistochemical analysis with an anti-lysozyme antibody demonstrated Paneth cells in the cancer tissues. AB-PAS-positive cells were also observed in high grade dysplastic aberrant crypt foci, which are considered to be preneoplastic lesions of the colon. Our results suggest that Paneth cell differentiation in colon epithelial cells could be an early morphological change in cryptic cells during colon carcinogenesis.