title: Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer.
abstract: 1,25 dihydroxyvitamin D (1,25(OH)2D), the active metabolite of vitamin D, and calcium regulate epidermal differentiation. 1,25(OH)2D exerts its effects through the vitamin D receptor (VDR), a transcription factor in the nuclear hormone receptor family, whereas calcium acts through the calcium sensing receptor (Casr), a membrane bound member of the G protein coupled receptor family. We have developed mouse models in which the Vdr and Casr have been deleted in the epidermis ((epid) Vdr (-∕-) and (epid) Casr (-∕-)). Both genotypes show abnormalities in calcium induced epidermal differentiation in vivo and in vitro, associated with altered hedgehog (HH) and β-catenin signaling that when abnormally expressed lead to basal cell carcinomas (BCC) and trichofolliculomas, respectively. The Vdr (-∕-) mice are susceptible to tumor formation following UVB or chemical carcinogen exposure. More recently we found that the keratinocytes from these mice over express long non-coding RNA (lncRNA) oncogenes such as H19 and under express lncRNA tumor suppressors such as lincRNA-21. Spontaneous tumors have not been observed in either the (epid) Vdr (-∕-) or (epid) Casr (-∕-). But in mice with epidermal specific deletion of both Vdr and Casr ((epid) Vdr (-∕-)/(epid) Casr (-∕-) [DKO]) tumor formation occurs spontaneously when the DKO mice are placed on a low calcium diet. These results demonstrate important interactions between vitamin D and calcium signaling through their respective receptors that lead to cancer when these signals are disrupted. The roles of the β-catenin, hedgehog, and lncRNA pathways in predisposing the epidermis to tumor formation when vitamin D and calcium signaling are disrupted will be discussed.
authors.affiliation: Departments of Medicine and Dermatology, VA Medical Center and University of California, San Francisco San Francisco, CA, USA.
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Bikle
authors.affiliation: Departments of Medicine and Dermatology, VA Medical Center and University of California, San Francisco San Francisco, CA, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Jiang
authors.affiliation: Departments of Medicine and Dermatology, VA Medical Center and University of California, San Francisco San Francisco, CA, USA.
authors.forename: Thai
authors.initials: T
authors.lastname: Nguyen
authors.affiliation: Departments of Medicine and Dermatology, VA Medical Center and University of California, San Francisco San Francisco, CA, USA.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Oda
authors.affiliation: Departments of Medicine and Dermatology, VA Medical Center and University of California, San Francisco San Francisco, CA, USA.
authors.forename: Chia-Ling
authors.initials: CL
authors.lastname: Tu
keywords: UVB; calcium sensing receptor; hedgehog; long non coding RNA; squamous cell carcinoma; vitamin D receptor; β–catenin