BCL­3 promotes cyclooxygenase­2/prostaglandin E2 signalling in colorectal cancer.

First discovered as an oncogene in leukaemia, recent reports highlight an emerging role for the proto­oncogene BCL­3 in solid tumours. Importantly, BCL­3 expression is upregulated in >30% of colorectal cancer cases and is reported to be associated with a poor prognosis. However, the mechanism by which BCL­3 regulates tumorigenesis in the large intestine is yet to be fully elucidated. In the present study, it was shown for the first time that knocking down BCL­3 expression suppressed cyclooxygenase­2 (COX­2)/prostaglandin E2 (PGE2) signalling in colorectal cancer cells, a pathway known to drive several of the hallmarks of cancer. RNAi­mediated suppression of BCL­3 expression decreased COX­2 expression in colorectal cancer cells both at the mRNA and protein level. This reduction in COX­2 expression resulted in a significant and functional reduction (30­50%) in the quantity of pro­tumorigenic PGE2 produced by the cancer cells, as shown by enzyme linked immunoassays and medium exchange experiments. In addition, inhibition of BCL­3 expression also significantly suppressed cytokine­induced (TNF­α or IL­1ß) COX­2 expression. Taken together, the results of the present study identified a novel role for BCL­3 in colorectal cancer and suggested that expression of BCL­3 may be a key determinant in the COX­2­meditated response to inflammatory cytokines in colorectal tumour cells. These results suggest that targeting BCL­3 to suppress PGE2 synthesis may represent an alternative or complementary approach to using non­steroidal anti­inflammatory drugs [(NSAIDs), which inhibit cyclooxygenase activity and suppress the conversion of arachidonic acid to prostaglandin], for prevention and/or recurrence in PGE2­driven tumorigenesis.