Vitamin D and Wnt/β-catenin Pathway in Colon Cancer: Role and regulation of DICKKOPF genes

Instituto de Investigaciones Biomédica Alberto Sols, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, E-28029 Madrid, Spain.
Anticancer research (Impact Factor: 1.83). 09/2008; 28(5A):2613-23.
Source: PubMed


Colorectal cancer is a major health problem worldwide. Aberrant activation of the Wingless-type mouse mammary tumour virus integration site family (Wnt)/beta-catenin signalling pathway due to mutation of adenomatous polyposis coli (APC), beta-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, 1alpha,25-dihydroxyvitamin D3 (1,25(OH)2D3) inhibits beta-catenin transcriptional activity by promoting vitamin D receptor (VDR) binding to beta-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/beta-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/beta-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/beta-catenin pathway in colon cancer cells that is in line with its protective effect against this neoplasia.

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    • "Interestingly, TGF-β treatment decreased levels of TCF-4 transcription factor that interacts with β-catenin to regulate DKK-1 expression [35]. Further, we found a significant reduction of TCF-4 in untreated as well as TGF-β -treated cells lacking β-catenin (Figure 4, E), thus being consistent to the fact that nuclear complex formation of β-catenin/TCF-4 takes place during canonical Wnt-signaling pathway [28], [35]. These data strongly suggest that β-catenin regulates Dkk-1 mRNA expression in IEC in response to TGF-β and is, similar to Dkk-1, involved in the regulation of TGF-β-induced IL-13 expression in IEC. "
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