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Carcinogenesis Advance Access published online on April 1, 2004
Carcinogenesis, doi:10.1093/carcin/bgh155
© 2004 by Oxford University Press
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© 2004 Oxford University Press

CARCINOGENESIS

Global gene expression analysis of rat colon cancers induced by a food-borne carcinogen, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

Kyoko Fujiwara 1, Masako Ochiai 1, Tsutomu Ohta 2, Misao Ohki 2, Hiroyuki Aburatani 3, Minako Nagao 1, Takashi Sugimura 1, and Hitoshi Nakagama 1*

1 Biochemistry Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
2 Medical Genetics Division, National Cancer Center Research Institute, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
3 Research Center for Advanced Science and Technology, The University of Tokyo, 4-6-1, Komaba, Meguroku, Tokyo 153-8904, Japan

* Corresponding author. E-mail: hnakagam{at}gan2.res.ncc.go.jp.

Received 24 October 2003 ; revised 11 March 2004 ; accepted 22 March 2004

Abstract

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 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 8,749 genes or ESTs on a high-density oligonucleotide microarray, 27 and 46 were over- and under-expressed, respectively, by 3-fold or greater 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 under-expressed. Interestingly, a subset of genes whose expression is characteristic of Paneth cells, i.e., defensins and matrilysin, were highly over-expressed in colon cancers. The presence of defensin 3 and 5 transcripts in cancer cells could also be confirmed by in situ mRNA hybridization. Furthermore, AB-PAS staining and immunohistochemical analysis with an anti-lysozyme antibody demonstrated Paneth cells in 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.

PhIP, colon cancer, gene expression profile, defensin, Paneth cells
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