Aberrant expression of the COX2/PGE₂ axis is induced by activation of the RAF/MEK/ERK pathway in BRAF^V595E canine urothelial carcinoma

Abstract

<jats:title>Abstract</jats:title><jats:p>Cancer-promoting inflammation is an important event in cancer development. The cyclooxygenase 2 (COX2)/prostaglandin E2 (PGE<jats:sub>2</jats:sub>) axis is a prominent inducer of inflammation. Canine urothelial carcinoma (cUC) uniquely overexpresses PGE<jats:sub>2</jats:sub> and is often managed well with COX inhibitor monotherapy. In most cases, cUC tissue harbours homologous human BRAF<jats:sup>V600E</jats:sup> mutation, which causes aberrant activation of the RAF/MEK/ERK pathway in human cancer. However, mechanisms underlying aberrant PGE<jats:sub>2</jats:sub> production and the importance of the <jats:italic>BRAF</jats:italic> mutation remain unclear. We show that activation of the RAF/MEK/ERK pathway in <jats:italic>BRAF</jats:italic> mutant cUC cells leads to COX2 overexpression and PGE<jats:sub>2</jats:sub> production. Drug screening revealed that treatment with inhibitors of the arachidonic acid cascade (FDR&lt;0.086), RAF/MEK/ERK pathway (FDR&lt;0.067), and p38/JNK pathway (FDR&lt;0.067) significantly reduced PGE<jats:sub>2</jats:sub> production in cUC cells. We also validated the association between RAF/MEK/ERK pathway activation and COX2/PGE<jats:sub>2</jats:sub> overexpression in <jats:italic>BRAF</jats:italic> mutant cUC cells using protein detection techniques. In histochemical analysis, <jats:italic>BRAF</jats:italic> mutant cUC tissue showed higher COX2 expression. Therefore, the driver mutation in the <jats:italic>BRAF</jats:italic> gene probably promotes tumour-promoting inflammation. These findings would benefit dogs suffering from cUC and can be extrapolated to human cancer. Finally, cUC can serve as a valuable model to elucidate the association between driver mutations and tumour-promoting inflammation.</jats:p>