Expression of cyclooxygenase-2 parallels expression of interleukin-1beta, interleukin-6 and NF-kappaB in human colorectal cancer

Elevated expression of cyclooxygenase-2 (COX-2), the inducible isoform of prostaglandin H synthase, has been found in several human cancers, including colorectal cancer (CRC). This appears as a rationale for the chemopreventive effects of non-steroidal anti-inflammatory drugs in CRC. However, the reason for COX-2 overexpression is not fully understood. In cell culture experiments, COX-2 can be induced by proinflammatory cytokines, such as interleukin (IL)-1beta and IL-6. A crucial step in this signalling pathway is thought to be activation of transcription factor NF-κB. Based on these findings, we hypothesized an association between COX-2 overexpression and expression of IL-1beta, IL-6 and the NF-κB subunit p65 in human CRC. To test the hypothesis, we performed immunohistochemistry for the respective antigens on colorectal cancer specimens, obtained by surgical resections from 21 patients with CRC. Immunohistochemical results were confirmed by examination of protein levels in tissue lysates and nuclear extracts using western blotting. Non-neoplastic tissue specimens resected well outside the tumour border served as controls. COX-2 expression was found to be markedly enhanced in the neoplastic epithelium compared with controls. This was paralleled by a significantly higher expression of IL-1beta, IL-6 and p65. Serial sections revealed consistent cellular colocalizations of respective antigens in the neoplastic epithelium. Statistically, a significant correlation between expression of COX-2 and IL-1beta, IL-6 and p65 was found. Comparable results were obtained for stromal cells like macrophages and myofibroblasts. Further examination of nuclear extracts from CRC-specimens by western blotting confirmed a higher content of p65 protein compared with non-neoplastic control tissues. Therefore, our study provides evidence for an association between expression of COX-2 and IL-1beta, IL-6 and p65 in human CRC. The results are consistent with the thesis that proinflammatory cytokines such as IL-1beta and IL-6 may be accountable for the overexpression of COX-2 in CRC. Finally, the study corroborates a role for NF-κB in the control of COX-2 gene transcription in CRC. Given an antiapoptotic role for COX-2 in tumour cells, inhibition of NF-κB may offer an important strategy to interfere with the development and progression of CRC.