Article

Vitamin D and Wnt/beta-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: 1.87). 28(5A):2613-23.
Source: PubMed

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.

1 Bookmark
 · 
95 Views
  • [Show abstract] [Hide abstract]
    ABSTRACT: Colorectal cancer is a major health problem world wide. Aberrant activation of the Wingless-type mouse mammary tumor virus integration site family(Wnt)/β-catenin signaling pathway is the most common and initial alteration in sporadic colorectal tumors. Numerous experimental studies have indicated that β-catenin is a key regulator of colorectal cancer. Indeed, β-catenin activity was shown to designate colon cancer stem cells (CSC) and is, therefore, an attractive target for new therapeutic agents. Thus, it is necessary to further understand its biology and search for effective therapy. Here we review the current literature regarding the functions of β-catenin control of intestinal cell fate and proliferation. Further, we provide a brief commentary on our current understanding of the role that β-catenin plays in colorectal tumor. These results show that β-catenin may serve as a good diagnosis biomarker of early-stage tumor development and a novel potential therapeutic target for colon cancer.
    Food and Chemical Toxicology 09/2014; 74. DOI:10.1016/j.fct.2014.08.013 · 2.61 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: WNT-β-catenin signalling is involved in a multitude of developmental processes and the maintenance of adult tissue homeostasis by regulating cell proliferation, differentiation, migration, genetic stability and apoptosis, as well as by maintaining adult stem cells in a pluripotent state. Not surprisingly, aberrant regulation of this pathway is therefore associated with a variety of diseases, including cancer, fibrosis and neurodegeneration. Despite this knowledge, therapeutic agents specifically targeting the WNT pathway have only recently entered clinical trials and none has yet been approved. This Review examines the problems and potential solutions to this vexing situation and attempts to bring them into perspective.
    dressNature Reviews Drug Discovery 07/2014; 13(7):513-32. DOI:10.1038/nrd4233 · 37.23 Impact Factor

Full-text

Download
102 Downloads
Available from
May 27, 2014