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) 2 D), suppresses β-catenin-mediated gene transcription by inducing vitamin D receptor (VDR)-β-catenin interactions. We examined whether acute treatment with 1,25(OH) 2 D 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) 2 D (1 μg/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) 2 D 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) 2 D 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) 2 D does not suppress colonic β-catenin signaling in vivo. This article is part of a special issue entitled ‘17th Vitamin D Workshop’.