Mechanisms of COX2 upregulation

COX-2 expression is regulated at transcriptional and post-transcrip-tional levels, and also by factors influencing the rate of protein synthesis and degradation.

The human COX-2 gene contains multiple transcription factor binding sites (60), for example, for cAMP (cAMP response element, CRE), inter-leukin-6 (IL6), and nuclear factor kB (NF-kB).

The chemical environment of malignancy is an ideal medium for COX-2 transcription. Dysregulated oncogenes, cytokines, growth factors and hormones, have all been shown to cause induction of COX-2 expression (61-66). In addition, loss of function of tumour suppressor genes may be an explanation for overexpression of COX-2. Mouse fibroblast cell lines engineered to express p53 demonstrate a large reduction in activity of the COX-2 promoter compared to cells which lack p53 expression constitu-tively (67). As we shall see, COX-2 expression can lead to an environment favouring increased transcription of the gene itself.

Once the gene is expressed, potential factors then come into play which can encourage the development and potentiation of a malignancy.

For ease of description, these can be classified as prostaglandin-dependent, and prostaglandin-independent mechanisms of carcinogenesis (Figure 2).

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