title: The effect of 1,25 dihydroxyvitamin D3 treatment on the mRNA levels of β catenin target genes in mice with colonic inactivation of both APC alleles.
abstract: In colon cancer, adenomatous polyposis coli (APC) inactivating gene mutations increase nuclear β-catenin levels and stimulate proliferation. In vitro, 1,25 dihydroxyvitamin D (1,25(OH)2D), suppresses β-catenin-mediated gene transcription by inducing vitamin D receptor (VDR)-β-catenin interactions. We examined whether acute treatment with 1,25(OH)2D could suppress β-catenin-mediated gene transcription in the hyperplastic colonic lesions of mice with colon-specific deletion of both APC gene alleles (CAC; APC(Δ580/Δ580)). At four weeks of age, CAC; APC(Δ580/Δ580) and control mice were injected with vehicle or 1,25(OH)2D (1μg/kg body weight) once a day for three days and then killed six hours after the last injection. mRNA levels of β-catenin target genes were elevated in the colon of CAC; APC(Δ580/Δ580) mice. 1,25(OH)2D increased 25 hydroxyvitamin D-24 hydroxylase mRNA levels in the colon of CAC; APC(Δ580/Δ580) and control mice indicating the treatments activated the VDR. However, 1,25(OH)2D had no effect on either β-catenin target gene mRNA levels or the proliferation index in CAC; APC(Δ580/Δ580) or control mice. VDR mRNA and protein levels were lower (-65% and -90%) in the colon of CAC; APC(Δ580/Δ580) mice compared to control mice, suggesting loss of colon responsiveness to vitamin D. Consistent with this, vitamin D-induced expression of transient receptor potential cation channel, subfamily V, member 6 mRNA was reduced in the colon of CAC; APC(Δ580/Δ580) mice. Our data show that short term exposure to 1,25(OH)2D does not suppress colonic β-catenin signaling in vivo. This article is part of a special issue entitled '17th Vitamin D Workshop'.
authors.affiliation: Purdue University Interdisciplinary Life Science Ph.D. program, Purdue University, West Lafayette, IN 47907, USA; Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA. Electronic address: mdesmet@iupui.edu.
authors.forename: Marsha
authors.initials: M
authors.lastname: DeWitt
authors.affiliation: Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA; Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA. Electronic address: johnson_robert_lee@lilly.com.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Johnson
authors.affiliation: Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; Department of Comparative Pathobiology, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Paul
authors.initials: P
authors.lastname: Snyder
authors.affiliation: Purdue University Interdisciplinary Life Science Ph.D. program, Purdue University, West Lafayette, IN 47907, USA; Purdue University Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA; Department of Nutrition Science, Purdue University, West Lafayette, IN 47907, USA. Electronic address: fleet@purdue.edu.
authors.forename: James C
authors.initials: JC
authors.lastname: Fleet
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000502:physiology*; D000818:Animals; D002117:Calcitriol / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D003108:Colonic Diseases / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation / Q000187:drug effects*; D051379:Mice; D018345:Mice, Knockout; D012333:RNA, Messenger / Q000235:genetics*; D060888:Real-Time Polymerase Chain Reaction; D018167:Receptors, Calcitriol / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D065668:Vitamin D3 24-Hydroxylase / Q000235:genetics*; D014815:Vitamins / Q000494:pharmacology; D051176:beta Catenin / Q000235:genetics*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D012333:RNA, Messenger; D018167:Receptors, Calcitriol; D014815:Vitamins; D051176:beta Catenin; D065668:Vitamin D3 24-Hydroxylase; D002117:Calcitriol
keywords: Cancer; Gene expression; Hyperplasia; Vitamin D