Effect of 1, 25-dihydroxyvitamin D3 on the Wnt pathway in non-malignant colonic cells. Issue 155 (January 2016)

• Record Type: Journal Article
• Authors: Gröschel, Charlotte; Aggarwal, Abhishek; Tennakoon, Samawansha; Höbaus, Julia; Prinz-Wohlgenannt, Maximilian; Marian, Brigitte; Heffeter, Petra; Berger, Walter; Kállay, Enikő
• Is Part Of: Journal of steroid biochemistry and molecular biology. Issue 155 Part B(2016)
• Page Start: 224
• Page End: 230
• Publication Date: 2016-01
• Subjects: CRC colorectal cancer -- APC adenomatous polyposis coli -- 1, 25-D3 1, 25-dihydroxyvitamin D3 -- CYP24A1 1, 25-D3 24-hydroxylase -- 25(OH)2D3 25-dihydroxyvitamin D3 -- TCF T-cell factor -- FAP familial adenomatous polyposis -- LGR5 leucine-rich G-protein coupled receptor 5 -- VDR vitamin D receptor; 1, 25-Dihydroxyvitamin D3 -- Colorectal cancer -- Chemoprevention -- Wnt pathway -- LGR5; Steroid hormones -- Periodicals; Biochemistry -- Periodicals; Hormones -- Periodicals; Molecular Biology -- Periodicals; Hormones stéroïdes -- Périodiques; Steroid hormones; Periodicals; 572.579
• DOI: 10.1016/j.jsbmb.2015.02.011
• Languages: English
• ISSNs: 0960-0760

Abstract

Highlights: 1, 25-D3 increases differentiation in the adenoma cell line LT97. 1, 25-D3 inhibits Wnt target gene expression. Vitamin D regulates the Wnt pathway in the healthy mouse colon. Abstract: Epidemiological studies suggest a correlation between vitamin D deficiency and colorectal cancer (CRC) incidence. The majority of sporadic tumors develop from premalignant lesions with aberrant activation of the Wnt/β-catenin signaling pathway. The adenoma cell line LT97 harbors an adenomatous polyposis coli (APC) mutation leading to constitutively active Wnt signaling. In these cells, expression of Wnt target genes leads to increased survival capacity. We hypothesized that 1, 25-dihydroyvitamin D3 (1, 25-D3 ), the active form of vitamin D3, promotes differentiation by modulating β-catenin/T-cell factor (TCF) 4-mediated gene transcription. The effect of dietary vitamin D on colonic Wnt signaling was investigated in mice fed either with 100 IU or 2500 IU vitamin D/kg diet. We examined the effect of 1, 25-D3 on differentiation by measuring alkaline phosphatase activity. We analyzed mRNA expression of Wnt target genes by real time qRT-PCR. The impact of 1, 25-D3 on β-catenin and TCF4 protein expression was assessed by western blot and immunohistochemistry. In LT97 cells, 1, 25-D3 increased cellular differentiation and reduced nuclear β-catenin levels. Further, 1, 25-D3 decreased mRNA expression of the Wnt target genes BCL-2, Cyclin D1, Snail1, CD44 and LGR5. In healthy colon of mice fed with high vitamin D diet, the mRNA levels of Wnt5a and ROR2, that promote degradation of β-catenin, were upregulated whereas β-catenin and TCF4 protein expression were decreased. In conclusion, 1, 25-D3 inhibits Wnt signaling even in nonmalignant cells underlining its importance in protection against colorectal tumorigenesis and early tumor progression. This article is part of a Special Issue entitled '17th Vitamin D Workshop'.