Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer.
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 sensin...
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2016-07-01
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doaj-89e6da50b4484b8db2dae8c6804d79eb2020-11-24T20:59:13ZengFrontiers Media S.A.Frontiers in Physiology1664-042X2016-07-01710.3389/fphys.2016.00296195871Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer.Daniel David Bikle0Yan Jiang1Thai Nguyen2Yuko Oda3Chia-ling Tu4University of California and VA Medical Center San FranciscoUniversity of California and VA Medical Center San FranciscoUniversity of California and VA Medical Center San FranciscoUniversity of California and VA Medical Center San FranciscoUniversity of California and VA Medical Center San Francisco1,25 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 (epidVdr-/- and epidCasr-/-). Both genotypes show abnormalities in calcium induced epidermal differentiation in vivo and in vitro, associated with altered hedgehog (HH) and beta-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 noncoding 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 epidVdr-/- or epidCasr-/-. But in mice with epidermal specific deletion of both Vdr and Casr (epidVdr-/- / epidCasr-/- [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 beta catenin, hedgehog, and lncRNA pathways in predisposing the epidermis to tumor formation when vitamin D and calcium signaling are disrupted will be discussed.http://journal.frontiersin.org/Journal/10.3389/fphys.2016.00296/fullSquamous cell carcinomaHedgehogvitamin D receptorCalcium sensing receptorlong non coding RNAUVB |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Daniel David Bikle Yan Jiang Thai Nguyen Yuko Oda Chia-ling Tu |
spellingShingle |
Daniel David Bikle Yan Jiang Thai Nguyen Yuko Oda Chia-ling Tu Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer. Frontiers in Physiology Squamous cell carcinoma Hedgehog vitamin D receptor Calcium sensing receptor long non coding RNA UVB |
author_facet |
Daniel David Bikle Yan Jiang Thai Nguyen Yuko Oda Chia-ling Tu |
author_sort |
Daniel David Bikle |
title |
Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer. |
title_short |
Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer. |
title_full |
Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer. |
title_fullStr |
Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer. |
title_full_unstemmed |
Disruption of Vitamin D and Calcium Signaling in Keratinocytes Predisposes to Skin Cancer. |
title_sort |
disruption of vitamin d and calcium signaling in keratinocytes predisposes to skin cancer. |
publisher |
Frontiers Media S.A. |
series |
Frontiers in Physiology |
issn |
1664-042X |
publishDate |
2016-07-01 |
description |
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 (epidVdr-/- and epidCasr-/-). Both genotypes show abnormalities in calcium induced epidermal differentiation in vivo and in vitro, associated with altered hedgehog (HH) and beta-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 noncoding 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 epidVdr-/- or epidCasr-/-. But in mice with epidermal specific deletion of both Vdr and Casr (epidVdr-/- / epidCasr-/- [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 beta catenin, hedgehog, and lncRNA pathways in predisposing the epidermis to tumor formation when vitamin D and calcium signaling are disrupted will be discussed. |
topic |
Squamous cell carcinoma Hedgehog vitamin D receptor Calcium sensing receptor long non coding RNA UVB |
url |
http://journal.frontiersin.org/Journal/10.3389/fphys.2016.00296/full |
work_keys_str_mv |
AT danieldavidbikle disruptionofvitamindandcalciumsignalinginkeratinocytespredisposestoskincancer AT yanjiang disruptionofvitamindandcalciumsignalinginkeratinocytespredisposestoskincancer AT thainguyen disruptionofvitamindandcalciumsignalinginkeratinocytespredisposestoskincancer AT yukooda disruptionofvitamindandcalciumsignalinginkeratinocytespredisposestoskincancer AT chialingtu disruptionofvitamindandcalciumsignalinginkeratinocytespredisposestoskincancer |
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