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Abstract

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  2. Abstract

Studies of colon carcinogenesis in animal models are very useful to elucidate mechanisms and provide pointers to potential prevention approaches in the human situation. In the rat colon carcinogenesis model induced by azoxymethane (AOM), we have documented frequent mutations of specific genes. K-ras mutations at codon 12 were found to be frequent in hyperplastic aberrant crypt foci (ACF) and large adenocarcinomas. In addition, mutations of the β-catenin gene in its GSK-3β phosphorylation consensus motif could also be identified in many adenomas and adenocarcinomas, and altered cellular localization of p-catenin protein was observed in all of the dysplastic ACF, adenomas and adenocarcinomas examined, indicating that activation of Wnt signaling by accumulation of β-catenin is a major mechanism in the AOM-induced colon carcinogenesis model. Frequent gene mutations of β-catenin and altered cellular localization of the protein are also features of AOM-induced colon tumors in mice. Expression of enzymes associated with inflammation, such as inducible nitric oxide synthase (INOS) and the inducible type of cyclooxyge-nase (COX), COX-2, is increased in AOM-induced rat colon carcinogenesis, and overproduction of nitric oxide (NO) and prostaglandins is considered to be involved in colon tumor development. We have demonstrated that increased expression of INOS is an early and important event occurring in step with β-catenin alteration in rat colon carcinogenesis. Activation of K-ras was also found to be involved in up-regulation of INOS in the presence of inflammatory stimuli. In addition, expression levels of prostaglandin E2 (PGE2) receptors may be altered in colon cancers. For example, the EP, and EP2 subtypes have been shown to be up-regulated and EP3 down-regulated in AOM-induced colon cancers in rats and mice. EP, and EP4 appear to be involved in ACF formation, while alteration in EP2 and EP3 is considered to contribute to later steps in colon carcinogenesis. Increased expression of some other gene products, such as the targets of Wnt/β-catenin signaling, have also been reported. The further accumulation of data with this chemically-induced animal colon carcinogenesis model should provide useful information for understanding colorectal neoplasia in man.

Abbreviations:
AOM

azoxymethane

INOS

inducible nitric oxide synthase

COX

cyclooxygenase

NO

nitric oxide

ACF

aberrant crypt foci

PGE2

prostaglandin E2

MNU

methylnitrosourea

PhIP

2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine

SSCP

single strand conformation polymorphism

IL-1β

interleukin-1β

LPS

lipopolysaccharide

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