EP1-4 subtype, COX and PPAR gamma 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 EP(1-4) 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. EP(1) and EP(2) subtype receptor protein was highly present in tumor cells, EP(3) occurred occasionally and EP(4) was not visible. PPAR gamma, EP(2) and EP(4) 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 EP(2) 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. EP(1-4) 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 EP(1-4) subtype receptors, particularly EP(2), predict disease-specific mortality in colorectal cancer.

Nyckelord

Adult

Aged

Aged

80 and over

Colorectal Neoplasms/genetics/metabolism/*pathology

Cyclooxygenase 1/genetics/metabolism

Cyclooxygenase 2/genetics/metabolism

Gene Expression Regulation

Neoplastic

Humans

Immunohistochemistry

Kaplan-Meiers Estimate

Middle Aged

Multivariate Analysis

PPAR gamma/*genetics/metabolism

Prognosis

Prostaglandin-Endoperoxide Synthases/*genetics/metabolism

RNA

Messenger/genetics/metabolism

Receptors

Prostaglandin E/*genetics/metabolism

Reverse Transcriptase Polymerase Chain Reaction

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