1α,25(OH)2-dihydroxyvitamin D3/VDR protects the skin from UVB-induced tumor formation by interacting with the β-catenin pathway

Abstract

Ultra violet (UV) irradiation, in particular UVB, is the single most important carcinogen for skin tumor formation. UVB induces genetic mutations and immune suppression, which lead to abnormal cell proliferation and eventually tumor formation. Previously studies from our group and others demonstrated that both global and epidermal specific VDR knock out mice are predisposed to either chemical (DMBA)- or long-term UVB-induced skin tumor formation, paralleled by an increase in β-catenin signaling. Using primary cultured human keratinocytes, we further demonstrated that 1,25(OH)2-dihydroxyvitamin D3 (1,25(OH)2D3) suppresses cyclin D1 and Gli1 which are regulated by β-catenin/TCF signaling and have a critical role in epidermal carcinogenesis. Blockage of VDR by siRNA resulted in hyperproliferation of keratinocytes, and increased expression of cyclin D1 and Gli1. In addition, we also showed that 1,25(OH)2D3/VDR directly regulates transcriptional activity of β-catenin/TCF signaling using the -catenin reporter TopGlow. Using K14 driven tamoxifen-induced cre recombinase to delete both VDR and β-catenin in keratinocytes of mice following the first hair follicle cycle, we found that ablation of epidermal specific β-catenin cannot rescue VDR null mice from UVB-induced skin tumor formation. Further study using VDR or β-catenin single null mice is necessary to compare with the data from double null mice. This article is part of a Special Issue entitled 'Vitamin D Workshop'.

Fig. 1

Generation of conditional VDR and β-catenin null mice. (A and B) The gene-targeting strategy to delete VDR or β-catenin from keratinocytes by using. Cre-loxP system. (C and D). Decreased expression of VDR or β-catenin mRNA was shown by RT-qPCR. (E) Method of UVB-induced skin tumor formation in K14 driven, TM-induced VDR and β-catenin null mice.

Fig. 2

Conditional deletion of VDR and β-catenin in epidermis promotes UVB-induced skin tumors. (A) The whole body of DKO mouse shows pigmentation (arrow) and hair, two solid dark-brown tumors (B and D) and one white, exophytic tumor (C). (E) The graph shows the increased rate (%) of skin tumor formation in DKO vs. WT control.