Aberrant expression of the COX2/PGEaxis is induced by activation of the RAF/MEK/ERK pathway in BRAFcanine urothelial carcinoma.

Abstract

Cancer-promoting inflammation is an important event in cancer development. Canine urothelial carcinoma (cUC) overexpresses prostaglandin E(PGE) and has a unique sensitivity to cyclooxygenase 2 (COX2)-inhibiting therapy. In addition, majority of cUC harbour BRAFmutation. However, mechanisms underlying aberrant PGEproduction in BRAFcUC patients remain unclear. Drug screening revealed that inhibition of RAF/MEK/ERK pathway, p38 and JNK pathway reduced PGEproduction in cUC cells. By pharmacological inhibition of the multiple components in the pathway, activation of the ERK MAPK pathway was shown to mediate overexpression of COX2 and production of PGEin BRAFcUC cells. In silico gain-of-function analysis of the BRAF mutation also implicated involvement of mutation in the process. The positive association between ERK activation and COX2 expression was further validated in the clinical patients. Moreover, it was also suggested that p38 and JNK regulates PGEproduction independently of ERK pathway, possibly through COX2-dependent and COX1-/COX2- independent manner, respectively. In conclusion, this study demonstrated that activation of ERK induces production of PGEin BRAFcUC cells, which is also independently regulated by p38 and JNK. With its unique vulnerability to COX-targeted therapy, BRAFcUC may serve as a valuable model to study the tumour-promoting inflammation.