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Connexin43 is overexpressed in Apc(Min/+)-mice adenomas and colocalises with COX-2 in myofibroblasts

Connexin43 is overexpressed in Apc(Min/+)-mice adenomas and colocalises with COX-2 in myofibroblasts

International Journal of Cancer 116(3): 351-358

The expression of gap junction proteins, connexins, in the intestine and their role in tumorigenesis are poorly characterised. Truncating mutations in the tumour suppressor gene adenomatous polyposis coli (APC) are early and important events, both in inheritable (familial adenomatous polyposis, FAP) and spontaneous forms of intestinal cancer. Multiple intestinal neoplasia (Min) mice, a FAP model with inherited heterozygous mutation in Ape, spontaneously develop numerous intestinal adenomas. We recently reported reduced expression of connexin32 in Paneth cells of Min-mice. We further examine the expression of connexin43 (Cx43) and other connexins as a function of heterozygous and homozygous Ape mutation in normal intestinal tissues and adenomas of Min-mice. Qualitative analysis of connexin mRNA in intestine revealed a similar expression pattern in Min- and wildtype (wt) mice. Connexin26 and connexin40 proteins were found in equal amounts in Min and wt epithelia of large and small intestine, respectively. Interestingly, the connexin43 level was increased in the stroma of Min-mice adenomas, in close proximity to epithelial cells with nuclear beta-catenin staining. Cx43 and COX-2 were located to the same areas of the adenomas, and immunostaining exhibited coexpression in the myofibroblasts. Prostaglandin E2 induces Cx43 expression and COX-2 is the rate-limiting enzyme in the prostaglandin synthesis. However, the COX-2-specific inhibitor, celecoxib, did not reduce Cx43 expression. Although both Cx43 and COX-2 are target genes for beta-catenin, they were overexpressed in stromal cells but not in epithelial tumour cells. We hypothesise that gap junctions may be of importance in the transfer of signals between epithelium and stroma. (C) 2005 Wiley-Liss, Inc.

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Accession: 011895022

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PMID: 15800939

DOI: 10.1002/ijc.21025

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