Coordinate regulation of cyclooxygenase-2 and TGF-β1 in replication error-positive colon cancer and azoxymethane-induced rat colonic tumors

Evidence is accumulating which indicates that cyclo-oxygenase-2 (COX-2) is involved in the pathogenesis of colorectal cancer. We evaluated the expression of COX-2 in replication error-positive (RER) colon cancers, colon cancers metastatic to liver and azoxymethane (AOM)induced rat colonic tumors. Immunohistochemistry showed that COX-2 was low to undetectable in normal human mucosa, but abundant in the RER adenocarcinomas we examined. COX-2 immunoreactivity in metastatic colon cancers was less abundant, but clearly detectable. In the colon of AOM-treated rats, COX-2 protein was not detectable in normal mucosa, but present in most of the epithelial cells comprising the tumors. The TGF-beta 1 staining pattern in these human and rat tumors was similar to that observed for COX-2, The role of TGF-beta in RER adenocarcinomas is complex because of the increased mutation rate of TGF-beta type IT receptors, Northern analysis showed abundant TGF-beta 1 mRNA in AOM-induced tumors, but not in paired mucosa, TGF-beta 1 induced the expression of COX-2 mRNA and protein in intestinal epithelial cells (IEC-6), Chronic TGF-beta 1 treatment caused a TGF-beta-dependent overexpression of COX-2 in rat intestinal epithelial cells (RIE-1), TGF-beta 1 may regulate COX-2 expression during the colonic adenoma to carcinoma sequence.