EP1-4 subtype, COX and PPARγ receptor expression in colorectal cancer in prediction of disease-specific mortality

The importance of prostaglandins in tumor growth and progression is well recognized, including antineoplastic activities by cyclooxygenase (COX) inhibitors. Variation in treatment response to COX inhibition has questioned differences in expression of cell surface and nuclear membrane receptors among tumors with different disease progression. The purpose of this study was to evaluate whether EP1-4 subtype, PPAR gamma receptor and COX-1/COX-2 expression in colorectal cancer are related to tumor-specific mortality. Reverse transcription-polymerase chain reaction and immunohistochemistry were used to demonstrate expression and protein appearance in tumor tissue compared with normal colon tissue. EP1 and EP2 subtype receptor protein was highly present in tumor cells, EP3 occurred occasionally and EP4 was not visible. PPAR gamma, EP2 and EP4 mRNA were significantly higher in normal colon tissue compared with tumor tissue, without any distinct relationship to Dukes A-D tumor stage. Multivariate analyses indicated that increased tumor tissue EP2 and COX-2 expression predicted poor survival (p < 0.001). COX-1 expression was significantly higher than COX-2 expression in normal colon tissue. Average COX-2 mRNA was not increased in tumor tissue compared with normal colon. However, most tumor cells stained positive for COX-2 protein, which was low or undetectable in normal mucosa cells. COX-1 protein was preferentially visible in stroma. EPI-4 subtype receptor mRNAs were generally positively correlated to both COX-1 and COX-2 in tumor tissue, but not in normal colon. Our results imply that both prostaglandin production (COX-2) and signaling via EP1-4 subtype receptors, particularly EP2, predict disease-specific mortality in colorectal cancer (c) 2007 Wiley-Liss, Inc.