RESUMO
BACKGROUND: Most colorectal cancers (CRC) arise sporadically from precursor lesions: colonic polyps. Polyp resection prevents progression to CRC. Risk of future polyps is proportional to the number and size of polyps detected at screening, allowing identification of high-risk individuals who may benefit from effective chemoprophylaxis. We aimed to investigate the potential of 5-aminosalicylic acid (5-ASA), a medication used in the treatment of ulcerative colitis, as a possible preventative agent for sporadic CRC. METHODS: Human colorectal adenoma (PC/AA/C1, S/AN/C1 and S/RG/C2), transformed adenoma PC/AA/C1/SB10 and carcinoma cell lines (LS174T and SW620) were treated with 5-ASA. The effect on growth in two- and three-dimensional (3D) culture, ß-catenin transcriptional activity and on cancer stemness properties of the cells were investigated. RESULTS: 5-ASA was shown, in vitro, to inhibit the growth of adenoma cells and suppress ß-catenin transcriptional activity. Downregulation of ß-catenin was found to repress expression of stem cell marker LGR5 (leucine-rich G protein-coupled receptor-5) and functionally suppress stemness in human adenoma and carcinoma cells using 3D models of tumorigenesis. CONCLUSIONS: 5-ASA can suppress the cancer stem phenotype in adenoma-derived cells. Affordable and well-tolerated, 5-ASA is an outstanding candidate as a chemoprophylactic medication to reduce the risk of colorectal polyps and CRC in those at high risk.
Assuntos
Adenoma/patologia , Neoplasias Colorretais/patologia , Mesalamina/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Adenoma/tratamento farmacológico , Adenoma/genética , Adenoma/prevenção & controle , Carcinogênese/efeitos dos fármacos , Carcinogênese/genética , Carcinogênese/patologia , Carcinoma/genética , Carcinoma/patologia , Carcinoma/prevenção & controle , Linhagem Celular Tumoral , Transformação Celular Neoplásica/efeitos dos fármacos , Transformação Celular Neoplásica/genética , Quimioprevenção/métodos , Colite Ulcerativa/tratamento farmacológico , Colite Ulcerativa/genética , Colite Ulcerativa/patologia , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Neoplasias Colorretais/prevenção & controle , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Humanos , Mesalamina/uso terapêutico , Células-Tronco Neoplásicas/fisiologia , Via de Sinalização Wnt/efeitos dos fármacos , Via de Sinalização Wnt/genéticaRESUMO
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.