Upregulation of cyclooxygenase-2 is accompanied by increased expression of nuclear factor-κB and IκB kinase-α in human colorectal cancer epithelial cells

Abstract

Cyclooxygenase-2 (COX-2) is selectively overexpressed in colorectal tumours. The mechanism of COX-2 induction is not fully understood, but requires de novo messenger RNA and protein synthesis, indicating regulation at the transcriptional level. Sequence analysis of the 5′-flanking region of the COX-2 gene shows two nuclear factor-κB (NF-κB) sites. Inhibition of this protein in model cell culture systems attenuates COX-2 expression and implies that NF-κB plays an important role in COX-2 induction. We measured COX-2, NF-κB and IκB kinase α (IKKα) protein expression in matched colonic biopsy samples comprising both nontumour and adjacent turnout tissue from 32 colorectal cancer patients using immunohistochemistry. There was none or very little expression of COX-2, NF-κB and IKKα in non-neoplastic colon epithelial cells, while the expression of all three of these proteins was significantly increased (P < 0.05, Wilcoxon's signed rank test) in adjacent cancerous cells. Moreover, all three proteins were found to be coexpressed in the neoplastic epithelium, with the expression of COX-2 and NF-κB highly correlated (Pearson's correlation, P < 0.005). There was no apparent correlation between enhanced COX-2, NF-κB or IKKα expression and tumour Dukes' stages. Our results are compatible with the hypothesis that IKKα and NF-κB are involved in COX-2 induction in these tumours and the lack of association between COX-2 expression and severity of disease as measured by Dukes' stage is consistent with the proposal that COX-2 expression is an early postinitiation event. © 2003 Cancer Research UK.