title: Vitamin D3 inhibits hedgehog signaling and proliferation in murine Basal cell carcinomas.
abstract: Constitutive Hedgehog (HH) signaling underlies several human tumors, including basal cell carcinoma (BCC). Recently, Bijlsma and colleagues reported a new biologic function for vitamin D3 in suppressing HH signaling in an in vitro model system. On the basis of that work, we have assessed effects of vitamin D3 on HH signaling and proliferation of murine BCCs in vitro and in vivo. We find that indeed in BCC cells, vitamin D3 blocks both proliferation and HH signaling as assessed by mRNA expression of the HH target gene Gli1. These effects of vitamin D3 on Gli1 expression and on BCC cell proliferation are comparable to the effects of cyclopamine, a known inhibitor of the HH pathway. These results are specific for vitamin D3, because the precursor 7-dehydrocholesterol and the downstream products 25-hydroxy vitamin D3 [25(OH)D] and 1,25-dihydroxy vitamin D3 [1,25(OH)(2)D] are considerably less effective in reducing either Gli1 mRNA or cellular proliferation. Moreover, these effects seem to be independent of the vitamin D receptor (VDR) because short hairpin RNA knockdown of VDR does not abrogate the anti-HH effects of D3 despite reducing expression of the VDR target gene 24-hydroxylase. Finally, topical vitamin D3 treatment of existing murine BCC tumors significantly decreases Gli1 and Ki67 staining. Thus, topical vitamin D3 acting via its HH inhibiting effect may hold promise as an effective anti-BCC agent.
authors: Department of Dermatology, Stanford University School of Medicine, Redwood City, CA 94063-5334, USA. tangy@stanford.edu
authors: Jean Y
authors: JY
authors: Tang
authors: Tony Zheng
authors: TZ
authors: Xiao
authors: Yuko
authors: Y
authors: Oda
authors: Kris S
authors: KS
authors: Chang
authors: Elana
authors: E
authors: Shpall
authors: Angela
authors: A
authors: Wu
authors: Po-Lin
authors: PL
authors: So
authors: Jennifer
authors: J
authors: Hebert
authors: Daniel
authors: D
authors: Bikle
authors: Ervin H
authors: EH
authors: Epstein
mesh_terms: D000818:Animals; D015153:Blotting, Western; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D002280:Basal Cell Carcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D002454:Cell Differentiation / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects*; D002478:Cells, Cultured; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002762:Cholecalciferol / Q000494:pharmacology*; D053823:Hedgehog Proteins / Q000235:genetics / Q000378:metabolism*; D007124:Immunoenzyme Techniques; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism; D051741:Kruppel-Like Transcription Factors / Q000235:genetics / Q000378:metabolism; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D051379:Mice; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D018167:Receptors, Calcitriol / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013250:Steroid Hydroxylases / Q000235:genetics / Q000378:metabolism; D065668:Vitamin D3 24-Hydroxylase; D000071676:Zinc Finger Protein GLI1
chemical_list: D050071:Bone Density Conservation Agents; C498520:Gli1 protein, mouse; D053823:Hedgehog Proteins; D051741:Kruppel-Like Transcription Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D018167:Receptors, Calcitriol; D000071676:Zinc Finger Protein GLI1; D002762:Cholecalciferol; D013250:Steroid Hydroxylases; D065668:Vitamin D3 24-Hydroxylase