title: Effect of 1,25-dihydroxyvitamin D3 on the Wnt pathway in non-malignant colonic cells.
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'.
authors.affiliation: Department of Pathophysiology and Allergy Research, Comprehensive Cancer Center, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Gröschel
authors.affiliation: Department of Pathophysiology and Allergy Research, Comprehensive Cancer Center, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
authors.forename: Abhishek
authors.initials: A
authors.lastname: Aggarwal
authors.affiliation: Department of Pathophysiology and Allergy Research, Comprehensive Cancer Center, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
authors.forename: Samawansha
authors.initials: S
authors.lastname: Tennakoon
authors.affiliation: Department of Pathophysiology and Allergy Research, Comprehensive Cancer Center, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Höbaus
authors.affiliation: Department of Pathophysiology and Allergy Research, Comprehensive Cancer Center, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria.
authors.forename: Maximilian
authors.initials: M
authors.lastname: Prinz-Wohlgenannt
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Marian
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria; Research Platform ``Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Petra
authors.initials: P
authors.lastname: Heffeter
authors.affiliation: Department of Medicine I, Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, A-1090 Vienna, Austria; Research Platform ``Translational Cancer Therapy Research", Vienna, Austria.
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.affiliation: Department of Pathophysiology and Allergy Research, Comprehensive Cancer Center, Medical University of Vienna, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Electronic address: enikoe.kallay@meduniwien.ac.at.
authors.forename: Enikő
authors.initials: E
authors.lastname: Kállay
mesh_terms: D000469:Alkaline Phosphatase / Q000235:genetics / Q000378:metabolism; D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D003106:Colon / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D005786:Gene Expression Regulation; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D000073940:Transcription Factor 4; D014807:Vitamin D / Q000031:analogs & derivatives* / Q000494:pharmacology; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics / Q000378:metabolism; D051153:Wnt Proteins / Q000235:genetics* / Q000378:metabolism; D060449:Wnt Signaling Pathway; D000071818:Wnt-5a Protein; D051176:beta Catenin / Q000235:genetics* / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C495267:CTNNB1 protein, mouse; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D051153:Wnt Proteins; D000071818:Wnt-5a Protein; C438615:Wnt5a protein, mouse; D051176:beta Catenin; C118756:dihydroxy-vitamin D3; D014807:Vitamin D; C585550:Cyp24a1 protein, mouse; D065668:Vitamin D3 24-Hydroxylase; D000469:Alkaline Phosphatase
keywords: 1,25-Dihydroxyvitamin D(3); Chemoprevention; Colorectal cancer; LGR5; Wnt pathway