Comparative global gene expression patterns of colonic epithelium in azoxymethane-induced carcinogenesis in rats and colorectal cancer in humans
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Azoxymethane (AOM) induced carcinogenesis in rats is an important model of human colorectal cancer (CRC). Using microarrays, gene expression changes in the rat colonic epithelium immediately after AOM injection (Acute model) and in AOM-induced tumours (Cancer model, 27 weeks after exposure) were compared to those occurring in human colorectal cancer. In rats, global gene expression in normal proximal versus distal rat colonic tissue differed markedly in both models. Rat tumours from different regions of the colon showed limited positional variability in gene expression. Therefore, loss of proximal/distal ‘site of origin’ signatures in tumours is an important consequence of AOM-induced carcinogenesis. In the Acute model, AOM exposure induced substantial changes in gene expression in the colonic epithelium. Whilst some of these changes were still apparent in the Cancer model, they were considerably reduced; suggesting repair has occurred in the damaged epithelial cells that did not progress into tumours. The tumour gene expression was radically different to the apparently ‘normal’ colonic epithelium. A comparative genomics in silico tool was developed to compare the rat microarray data derived from normal and carcinogen exposed colonic epithelium or tumour tissue with related data from positionally-matched human CRC and normal colonic epithelium. Gene expression networks were devised for both models. There was some overlap (41% and 21% respectively) when differentially expressed genes in the rat Acute and Cancer models were compared to their human orthologs differentially expressed in cancer. Networks prepared for these conserved genes further highlight similarities between these rat models and human CRC.