First discovered as an oncogene in leukaemia, recent reports highlight an emerging role for the proto-oncogene BCL-3 in solid tumours. Importantly, BCL-3 is highly expressed in >30% of colorectal cancers and reported to be associated with poor prognosis. However, the mechanism by which BCL-3 regulates tumorigenesis in the large bowel is yet to be fully elucidated. Here we show for the first time that depleting BCL-3 can suppress cyclooxygenase-2 (COX-2)/Prostaglandin E2 (PGE2) signalling in colorectal cancer cells, a pathway known to drive many of the hallmarks of cancer. RNAi-mediated suppression of BCL-3 expression decreased COX-2 expression in colorectal cancer cells both at the mRNA and protein level. This reduction in COX-2 expression led to a significant and functional reduction (30-50%) in the amount of pro-tumorigenic PGE2 produced by the cancer cells, as shown by enzyme linked immunoassay and medium exchange experiments. In addition, inhibition of BCL-3 expression also significantly suppressed cytokine-induced (TNF-α or IL-1β) COX-2 expression. Taken together, this report identifies a novel role for BCL-3 in colorectal cancer and suggests that expression of BCL-3 may be a key determinant in the COX-2 response to inflammatory cytokines in colorectal tumour cells. We propose that targeting BCL-3 to suppress PGE2 synthesis may represent an alternative or complementary approach to using NSAIDs for prevention and/or recurrence in PGE2-driven tumorigenesis.
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