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Vitamin D and Wnt/β-catenin pathway in colon cancer: Role and regulation of DICKKOPF genes

AuthorsPendás-Franco, Natalia; Aguilera, Óscar ; Pereira, Fábio; González-Sancho, José Manuel ; Muñoz Terol, Alberto
Issue Date2008
PublisherInternational Institute of Anticancer Research
CitationAnticancer Research 28(5A): 2613-2623 (2008)
AbstractColorectal cancer is a major health problem worldwide. Aberrant activation of the Wingless-type mouse mammary tumour virus integration site family (Wnt)/β-catenin signalling pathway due to mutation of adenomatous polyposis coli (APC), β-catenin (CTNNB1) or AXIN genes is the most common and initial alteration in sporadic colorectal tumours. Numerous epidemiological and experimental studies have indicated a protective action of vitamin D against colorectal cancer. Previous work has demonstrated that the most active vitamin D metabolite, 1α,25-dihydroxyvitamin D3 (125(OH) 2D3) inhibits β-catenin transcriptional activity by promoting vitamin D receptor (VDR) binding to β-catenin and the induction of E-cadherin expression. Recently, 1,25(OH)2D3 has been shown to distinctly regulate two genes encoding the extracellular Wnt inhibitors DICKKOPF-1 and DICKKOPF-4 (DKK-1, DKK-4). By an indirect transcriptional mechanism, 1,25(OH)2D3 increases the expression of DKK-1 RNA and protein, which acts as a tumour suppressor in human colon cancer cells harbouring endogenous mutations in the Wnt/β-catenin pathway. In contrast, 1,25(OH)2D3 represses DKK-4 transcription by inducing direct VDR binding to its promoter. Unexpectedly, DKK-4 is a target of the Wnt/β-catenin pathway and is up-regulated in colorectal tumours, and it has been shown to increase cell migration and invasion and to promote a proangiogenic phenotype. Together, these results show that 1,25(OH) 2D3 exerts a complex set of regulatory actions leading to the inhibition of the Wnt/β-catenin pathway in colon cancer cells that is in line with its protective effect against this neoplasia.
Identifiersissn: 0250-7005
e-issn: 1791-7530
Appears in Collections:(IIBM) Artículos
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