title: Overexpression of hedgehog signaling is associated with epidermal tumor formation in vitamin D receptor-null mice.
abstract: The vitamin D receptor (VDR) ligand, 1,25 dihydroxyvitamin D(3) (1,25(OH)(2)D(3)), reduces proliferation and enhances differentiation, and thus has been investigated for a role in preventing or treating cancer. Mice deficient for the VDR display a hyperproliferative response in the hair follicle and epidermis and decreased epidermal differentiation. Unlike their wild-type littermates, when treated with 7,12 dimethylbenzanthracene (DMBA) or UVB, they develop skin tumors, including some characteristic of overexpression of the hedgehog (Hh) pathway. Both the epidermis and utricles of the VDR-null animals overexpress elements of the Hh pathway (sonic hedgehog (Shh) 2.02-fold, patched1 1.58-fold, smoothened 3.54-fold, glioma-associated oncogene homolog (Gli)1 1.17-fold, and Gli2 1.66-fold). This overexpression occurs at an age (11 weeks) at which epidermal hyperproliferation is most visible and is spatially controlled in the epidermis. DMBA- or UVB-induced tumors in the VDR-null mice also overexpress elements of this pathway. Moreover, 1,25(OH)(2)D(3) downregulates the expression of some members of the Hh pathway in an epidermal explants culture system, suggesting a direct regulation by 1,25(OH)(2)D(3). Our results suggest that increased expression of Shh in the keratinocytes of the VDR-null animal activates the Hh pathway, predisposing the skin to the development of both malignant and benign epidermal neoplasms.
authors.affiliation: Endocrine Unit, Department of Dermatology, University of California, San Francisco, San Francisco, California 94121, USA.
authors.forename: Arnaud E
authors.initials: AE
authors.lastname: Teichert
authors.forename: Hashem
authors.initials: H
authors.lastname: Elalieh
authors.forename: Peter M
authors.initials: PM
authors.lastname: Elias
authors.forename: JoEllen
authors.initials: J
authors.lastname: Welsh
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
mesh_terms: D015127:9,10-Dimethyl-1,2-benzanthracene / Q000009:adverse effects / Q000494:pharmacology; D000818:Animals; D002117:Calcitriol / Q000378:metabolism; D002273:Carcinogens / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004817:Epidermis / Q000187:drug effects / Q000378:metabolism / Q000528:radiation effects; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018167:Receptors, Calcitriol / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology* / Q000528:radiation effects; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology*; D014466:Ultraviolet Rays / Q000009:adverse effects
chemical_list: D002273:Carcinogens; D053823:Hedgehog Proteins; D018167:Receptors, Calcitriol; D015127:9,10-Dimethyl-1,2-benzanthracene; D002117:Calcitriol