Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis
Open accessAbstract
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.
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UV can elicit the synthesis of vitamin D, an important molecule in calcium homeostasis of various types of skin cells contributing to DNA repair and immunomodulation.
“Furthermore, UV can elicit the synthesis of vitamin D, an important molecule in calcium homeostasis of various types of skin cells contributing to DNA repair and immunomodulation.”
From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [85]
Rates of thymine-dimer repair and UV-induced apoptosis in the epidermis of vitamin D receptor knockout mice are significantly lower than those in the epidermis of wild type mice.
“Rates of thymine-dimer repair and UV-induced apoptosis in the epidermis of vitamin D receptor (VDR) knockout mice have been found to be significantly lower than those in the epidermis of wild type mice [85].”
From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [85]
VDR plays a critical role in the repair and removal of severely damaged keratinocytes by UV exposure.
“Furthermore, UV-induced epidermal thickening has also been found to be attenuated in VDR(−/−) skin, indicating that VDR plays a critical role in the repair and removal of severely damaged keratinocytes by UV exposure [85].”
From Molecular Mechanisms of UV-Induced Apoptosis and Its Effects on Skin Residential Cells: The Implication in UV-Based Phototherapy (2013) · cites this paper as [85]
Cites
DNA damage induces phosphorylation of the amino terminus of p53
Siliciano, J. D., Canman, C. E., Taya, Y., Sakaguchi, K., Appella, E., & Kastan, M. B. (1997) · Genes & Development · doi:10.1101/gad.11.24.3471 · Cited by 818 · see citing works
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Molecular Mechanisms of Vitamin D Action
Haussler, M. R., Whitfield, G. K., Kaneko, I., Haussler, C. A., Hsieh, D., Hsieh, J.-C., & Jurutka, P. W. (2013) · Calcified Tissue International · doi:10.1007/s00223-012-9619-0 · Cited by 759 · see citing works
Lee, C.-H., Wu, S.-B., Hong, C.-H., Yu, H.-S., & Wei, Y.-H. (2013) · International Journal of Molecular Sciences · doi:10.3390/ijms14036414 · Cited by 271 · see citing works
Ansell, D. M., Kloepper, J. E., Thomason, H. A., Paus, R., & Hardman, M. J. (2011) · Journal of Investigative Dermatology · doi:10.1038/jid.2010.291 · Cited by 171 · see citing works
Dixon, K. M., Norman, A. W., Sequeira, V. B., Mohan, R., Rybchyn, M. S., Reeve, V. E., Halliday, G. M., & Mason, R. S. (2011) · Cancer Prevention Research · doi:10.1158/1940-6207.capr-11-0165 · Cited by 112 · see citing works
Vitamin D receptor, a tumor suppressor in skin
Bikle, D. D. (2015) · Canadian Journal of Physiology and Pharmacology · doi:10.1139/cjpp-2014-0367 · Cited by 101 · see citing works
Song, E. J., Gordon-Thomson, C., Cole, L., Stern, H., Halliday, G. M., Damian, D. L., Reeve, V. E., & Mason, R. S. (2013) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2012.11.003 · Cited by 65 · see citing works
Rybchyn, M. S., De Silva, W. G. M., Sequeira, V. B., McCarthy, B. Y., Dilley, A. V., Dixon, K. M., Halliday, G. M., & Mason, R. S. (2018) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2017.11.037 · Cited by 63 · see citing works
CYP11A1 in skin: an alternative route to photoprotection by vitamin D compounds
Tongkao-on, W., Carter, S., Reeve, V. E., Dixon, K. M., Gordon-Thomson, C., Halliday, G. M., Tuckey, R. C., & Mason, R. S. (2015) · The Journal of Steroid Biochemistry and Molecular Biology · doi:10.1016/j.jsbmb.2014.11.015 · Cited by 63 · see citing works
Demetriou, S. K., Ona-Vu, K., Teichert, A. E., Cleaver, J. E., Bikle, D. D., & Oh, D. H. (2012) · Journal of Investigative Dermatology · doi:10.1038/jid.2012.107 · Cited by 50 · see citing works
- Authors
- Ellison, T. I., Smith, M. K., Gilliam, A. C., & MacDonald, P. N.
- Affiliations
- Case Western Reserve University (US)
- Corresponding author
- MacDonald, Paul N.
- ORCID
- Smith, Molly K.
- Venue
- Journal of Investigative Dermatology
- Publisher
- Elsevier BV
- Published
- 2008-10
- Volume
- 128
- Issue
- 10
- Pages
- 2508-2517
- ISSN
- 0022-202X (ISSN-L)
- PMC
- PMC4127033
- OpenAlex
- W1978243004
- Cited by
- 159
- References
- 1
- Citations by year
- 2026: 4 · 2025: 1 · 2024: 3 · 2023: 5 · 2022: 7 · 2021: 8 · 2020: 9 · 2019: 5 · 2018: 5 · 2017: 7 · 2016: 10 · 2015: 6 · 2014: 18 · 2013: 10 · 2012: 20
- FWCI
- 9.49
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Journal of Investigative Dermatology (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- Case Western Reserve University
- Korea Electrotechnology Research Institute
- National Institutes of Health
- National Institute of General Medical Sciences (T32GM 08803, T32GM008803)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01-DK-53980, R01DK053980)
- National Institute of Arthritis and Musculoskeletal and Skin Diseases (AR639750)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Vitamin D Research Studies
- Health Sciences › Medicine › Dermatology › Skin Protection and Aging
- Health Sciences › Medicine › Epidemiology › Nonmelanoma Skin Cancer Studies
- Keywords
- vitamin D receptor, UV-induced skin carcinogenesis, 1,25-dihydroxyvitamin D3, CYP27B1, 25-hydroxyvitamin D3-1α-hydroxylase, VDR knockout mice, p53, UV-induced apoptosis, epidermal thickening, keratinocytes, skin cancer predisposition, hair cycle
- MeSH terms
- Adaptation, Physiological, Animals, Disease Susceptibility, Epidermis, Neoplasms, Radiation-Induced, Pyrimidine Dimers, Skin, Skin Neoplasms, Ultraviolet Rays, Vitamin D, Keratinocytes, Apoptosis, Receptors, Calcitriol, Mice, Knockout, Penetrance, Mice
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