Vitamin D and Wnt/beta-catenin Pathway in Colon Cancer: Role and Regulation of DICKKOPF Genes

作者：Pendas Franco Natalia; Aguilera Oscar; Pereira Fabio; Manuel Gonzalez Sancho Jose; Munoz Alberto^*

来源：Anticancer Research, 2008, 28(5A): 2613-2623.

• Vitamin D
• Wnt
• beta-catenin
• Dickkopf
• colon cancer
• review

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, 1 alpha,25-dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) 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)(2)D(3) 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)(2)D(3) 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)(2)D(3) 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)(2)D(3) 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.

• 出版日期2008-10