Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis.
1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) is the biologically active ligand for the vitamin D receptor (VDR). VDR(-/-) mice have a hair follicle-cycling defect resulting in alopecia. However, mice lacking 25-hydroxyvitamin D(3) 1alpha-hydroxylase (CYP27B1(-/-)), and having no circulating 1,25(OH)(2)D(3), have normal follicular function. These mouse models indicate that VDR functions independently of 1,25(OH)(2)D(3) in regulating hair-follicle cycling. Here, we show that VDR(-/-) mice rapidly develop chemically induced skin tumors, whereas CYP27B1(-/-) and wild-type mice do not, indicating that VDR, and not the 1,25(OH)(2)D(3) ligand, is essential for protection against skin tumorigenesis. Because the majority of human skin cancer results from exposure to UV, the susceptibility of VDR(-/-) mice to this carcinogen was also evaluated. VDR(-/-) mice developed UV-induced tumors more rapidly and with greater penetrance than did VDR(+/+) mice. p53 protein levels were upregulated at similar rates in UV-treated keratinocytes of VDR(-/-) and VDR(+/+) mice. However, rates of thymine-dimer repair and UV-induced apoptosis were significantly lower in VDR(-/-) epidermis compared with the wild type epidermis. UV-induced epidermal thickening was also attenuated in VDR(-/-) skin, indicating that VDR plays a critical role in the repair and removal of severely damaged keratinocytes and adaptation of the skin to chronic UV exposure.
Ellison
Tara I
TI
Department of Pharmacology, Case Western Reserve University, Cleveland, Ohio 44116, USA.
Smith
Molly K
MK
Gilliam
Anita C
AC
MacDonald
Paul N
PN
D000222:Adaptation, Physiological; D000818:Animals; D017209:Apoptosis; D004198:Disease Susceptibility; D004817:Epidermis / Q000503:physiopathology / Q000528:radiation effects; D015603:Keratinocytes / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D009381:Neoplasms, Radiation-Induced; D019683:Penetrance; D011740:Pyrimidine Dimers / Q000737:chemistry / Q000378:metabolism; D018167:Receptors, Calcitriol / Q000172:deficiency* / Q000378:metabolism; D012867:Skin / Q000473:pathology / Q000503:physiopathology / Q000528:radiation effects; D012878:Skin Neoplasms / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D014466:Ultraviolet Rays; D014807:Vitamin D / Q000031:analogs & derivatives / Q000235:genetics
D011740:Pyrimidine Dimers; D018167:Receptors, Calcitriol; C118756:dihydroxy-vitamin D3; D014807:Vitamin D