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Vitamin D and Wnt/beta-catenin pathway in colon cancer: role and regulation of DICKKOPF genes.
Anticancer Res. 2008 Sep-Oct; 28(5A):2613-23.AR

Abstract

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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Authors+Show Affiliations

Pendás-Franco N
Instituto de Investigaciones Biomédica Alberto Sols, Consejo Superior de Investigaciones Científicas, Universidad Autónoma de Madrid, E-28029 Madrid, Spain.
Aguilera O
No affiliation info available
Pereira F
No affiliation info available
González-Sancho JM
No affiliation info available
Muñoz A
No affiliation info available

MeSH

CalcitriolColonic NeoplasmsGene Expression Regulation, NeoplasticHumansIntercellular Signaling Peptides and ProteinsSignal TransductionWnt Proteinsbeta Catenin

Pub Type(s)

Journal Article
Review

Language

eng

PubMed ID

19035286

Citation

Pendás-Franco, Natalia, et al. "Vitamin D and Wnt/beta-catenin Pathway in Colon Cancer: Role and Regulation of DICKKOPF Genes." Anticancer Research, vol. 28, no. 5A, 2008, pp. 2613-23.
Pendás-Franco N, Aguilera O, Pereira F, et al. Vitamin D and Wnt/beta-catenin pathway in colon cancer: role and regulation of DICKKOPF genes. Anticancer Res. 2008;28(5A):2613-23.
Pendás-Franco, N., Aguilera, O., Pereira, F., González-Sancho, J. M., & Muñoz, A. (2008). Vitamin D and Wnt/beta-catenin pathway in colon cancer: role and regulation of DICKKOPF genes. Anticancer Research, 28(5A), 2613-23.
Pendás-Franco N, et al. Vitamin D and Wnt/beta-catenin Pathway in Colon Cancer: Role and Regulation of DICKKOPF Genes. Anticancer Res. 2008 Sep-Oct;28(5A):2613-23. PubMed PMID: 19035286.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Vitamin D and Wnt/beta-catenin pathway in colon cancer: role and regulation of DICKKOPF genes. AU - Pendás-Franco,Natalia, AU - Aguilera,Oscar, AU - Pereira,Fabio, AU - González-Sancho,José Manuel, AU - Muñoz,Alberto, PY - 2008/11/28/pubmed PY - 2008/12/17/medline PY - 2008/11/28/entrez SP - 2613 EP - 23 JF - Anticancer research JO - Anticancer Res VL - 28 IS - 5A N2 - 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. SN - 0250-7005 UR - https://www.unboundmedicine.com/medline/citation/19035286/Vitamin_D_and_Wnt/beta_catenin_pathway_in_colon_cancer:_role_and_regulation_of_DICKKOPF_genes_ L2 - http://ar.iiarjournals.org/cgi/pmidlookup?view=long&pmid=19035286 DB - PRIME DP - Unbound Medicine ER -