Skip to main content

Advertisement

SpringerLink
Log in

Protective actions of vitamin D in UVB induced skin cancer

  • Perspective
  • Published:
Photochemical & Photobiological Sciences Aims and scope Submit manuscript

Abstract

Non-melanoma skin cancers (NMSC) are the most common type of cancer, occurring at a rate of over 1 million per year in the United States. Although their metastatic potential is generally low, they can and do metastasize, especially in the immune compromised host, and their surgical treatment is often quite disfiguring. Ultraviolet radiation (UVR) as occurs with sunlight exposure is generally regarded as causal for these malignancies, but UVR is also required for vitamin D synthesis in the skin. Based on our own data and that reported in the literature, we hypothesize that the vitamin D produced in the skin serves to suppress UVR epidermal tumor formation. In this review we will first discuss the evidence supporting the conclusion that the vitamin D receptor (VDR), with or without its ligand 1,25-dihydroxyvitamin D, limits the propensity for cancer formation following UVR. We will then explore three potential mechanisms for this protection: inhibition of proliferation and stimulation of differentiation, immune regulation, and stimulation of DNA damage repair (DDR).

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. R. T. Greenlee, M. B. Hill-Harmon, T. Murray and M. Thun, Cancer statistics, Ca-Cancer J. Clin., 2001, 51, 15–36.

    Article  CAS  PubMed  Google Scholar 

  2. R. M. Lucas, A. J. McMichael, B. K. Armstrong and W. T. Smith, Estimating the global disease burden due to ultraviolet radiation exposure, Int. J. Epidemiol., 2008, 37, 654–667.

    Article  PubMed  Google Scholar 

  3. B. K. Armstrong and A. Kricker, The epidemiology of UV induced skin cancer, J. Photochem. Photobiol., B, 2001, 63, 8–18.

    Article  CAS  Google Scholar 

  4. D. R. English, B. K. Armstrong, A. Kricker, M. G. Winter, P. J. Heenan and P. L. Randell, Case-control study of sun exposure and squamous cell carcinoma of the skin, Int. J. Cancer, 1998, 77, 347–353.

    Article  CAS  PubMed  Google Scholar 

  5. S. Rosso, R. Zanetti, C. Martinez, M. J. Tormo, S. Schraub, H. Sancho-Garnier, S. Franceschi, L. Gafa, E. Perea, C. Navarro, R. Laurent, C. Schrameck, R. Talamini, R. Tumino and J. Wechsler, The multicentre south European study ‘Helios’. II: different sun exposure patterns in the aetiology of basal cell and squamous cell carcinomas of the skin, Br. J. Cancer, 1996, 73, 1447–1454.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. M. F. Holick, J. A. McLaughlin, M. B. Clark and S. H. Doppelt, Factors that influence the cutaneous photosynthesis of previtamin D3, Science, 1981, 211, 590–593.

    Article  CAS  PubMed  Google Scholar 

  7. M. F. Holick, J. A. McLaughlin, M. B. Clark, S. A. Holick, J. T. Potts, Jr., R. R. Anderson, I. H. Blank and J. A. Parrish, Photosynthesis of previtamin D3 in human and the physiologic consequences, Science, 1980, 210, 203–205.

    Article  CAS  PubMed  Google Scholar 

  8. M. F. Holick, N. M. Richtand, S. C. McNeill, S. A. Holick, J. W. Henley, J. T. Potts, Jr., Isolation and identification of previtamin D3 from the skin of exposed to ultraviolet irradiation, Biochemistry, 1979, 18, 1003–1008.

    Article  CAS  PubMed  Google Scholar 

  9. A. R. Webb, L. Kline and M. F. Holick, Influence of season and latitude on the cutaneous synthesis of vitamin D3: exposure to winter sunlight in Boston and Edmonton will not promote vitamin D3 synthesis in human skin, J. Clin. Endocrinol. Metab., 1988, 67, 373–378.

    Article  CAS  PubMed  Google Scholar 

  10. D. D. Bikle, M. K. Nemanic, E. Gee and P. Elias, 1,25-Dihydroxyvitamin D3 production by human keratinocytes. Kinetics and regulation, J. Clin. Invest., 1986, 78, 557–566.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Z. Xie, S. J. Munson, N. Huang, A. A. Portale, W. L. Miller and D. D. Bikle, The mechanism of 1,25-dihydroxyvitamin D(3) autoregulation in keratinocytes, J. Biol. Chem., 2002, 277, 36987–36990.

    Article  CAS  PubMed  Google Scholar 

  12. D. D. Bikle, S. Pillai, E. Gee and M. Hincenbergs, Tumor necrosis factor-alpha regulation of 1,25-dihydroxyvitamin D production by human keratinocytes, Endocrinology, 1991, 129, 33–38.

    Article  CAS  PubMed  Google Scholar 

  13. D. D. Bikle, S. Pillai, E. Gee and M. Hincenbergs, Regulation of 1,25-dihydroxyvitamin D production in human keratinocytes by interferon-gamma, Endocrinology, 1989, 124, 655–660.

    Article  CAS  PubMed  Google Scholar 

  14. J. A. Eisman, T. J. Martin, I. MacIntyre and J. M. Moseley, 1,25-dihydroxyvitamin-D-receptor in breast cancer cells, Lancet, 1979, 2, 1335–1336.

    Article  CAS  PubMed  Google Scholar 

  15. A. V. Ratnam, D. D. Bikle, M. J. Su and S. Pillai, Squamous carcinoma cell lines fail to respond to 1,25-dihydroxyvitamin D despite normal levels of the vitamin D receptor, J. Invest. Dermatol., 1996, 106, 522–525.

    Article  CAS  PubMed  Google Scholar 

  16. J. Kamradt, L. Rafi, T. Mitschele, V. Meineke, B. C. Gartner, T. Wolfgang, M. F. Holick and J. Reichrath, Analysis of the vitamin D system in cutaneous malignancies, Recent Results Cancer Res., 2003, 164, 259–269.

    Article  CAS  PubMed  Google Scholar 

  17. K. Colston, M. J. Colston and D. Feldman, 1,25-dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture, Endocrinology, 1981, 108, 1083–1086.

    Article  CAS  PubMed  Google Scholar 

  18. C. Garland, R. B. Shekelle, E. Barrett-Connor, M. H. Criqui, A. H. Rossof and O. Paul, Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men, Lancet, 1985, 1, 307–309.

    Article  CAS  PubMed  Google Scholar 

  19. R. M. Bostick, J. D. Potter, T. A. Sellers, D. R. McKenzie, L. H. Kushi and A. R. Folsom, Relation of calcium, vitamin D, and dairy food intake to incidence of colon cancer among older women. The Iowa Women’s Health Study, Am. J. Epidemiol., 1993, 137, 1302–1317.

    Article  CAS  PubMed  Google Scholar 

  20. J. Kearney, E. Giovannucci, E. B. Rimm, A. Ascherio, M. J. Stampfer, G. A. Colditz, A. Wing, E. Kampman and W. C. Willett, Calcium, vitamin D, and dairy foods and the occurrence of colon cancer in men, Am. J. Epidemiol., 1996, 143, 907–917.

    Article  CAS  PubMed  Google Scholar 

  21. F. C. Garland, C. F. Garland, E. D. Gorham and J. F. Young, Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation, Prev. Med., 1990, 19, 614–622.

    Article  CAS  PubMed  Google Scholar 

  22. C. L. Hanchette and G. G. Schwartz, Geographic patterns of prostate cancer mortality. Evidence for a protective effect of ultraviolet radiation, Cancer, 1992, 70, 2861–2869.

    Article  CAS  PubMed  Google Scholar 

  23. R. M. van Dam, Z. Huang, E. Giovannucci, E. B. Rimm, D. J. Hunter, G. A. Colditz, M. J. Stampfer and W. C. Willett, Diet and basal cell carcinoma of the skin in a prospective cohort of men, Am. J. Clin. Nutr., 2000, 71, 135–141.

    Article  PubMed  Google Scholar 

  24. D. J. Hunter, G. A. Colditz, M. J. Stampfer, B. Rosner, W. C. Willett and F. E. Speizer, Diet and risk of basal cell carcinoma of the skin in a prospective cohort of women, Ann. Epidemiol., 1992, 2, 231–239.

    Article  CAS  PubMed  Google Scholar 

  25. M. A. Weinstock, M. J. Stampfer, R. A. Lew, W. C. Willett and A. J. Sober, Case-control study of melanoma and dietary vitamin D: implications for advocacy of sun protection and sunscreen use, J. Invest. Dermatol., 1992, 98, 809–811.

    Article  CAS  PubMed  Google Scholar 

  26. G. M. Zinser, J. P. Sundberg and J. Welsh, Vitamin D(3) receptor ablation sensitizes skin to chemically induced tumorigenesis, Carcinogenesis, 2002, 23, 2103–2109.

    Article  CAS  PubMed  Google Scholar 

  27. A. K. Indra, E. Castaneda, M. C. Antal, M. Jiang, N. Messaddeq, X. Meng, C. V. Loehr, P. Gariglio, S. Kato, W. Wahli, B. Desvergne, D. Metzger and P. Chambon, Malignant transformation of DMBA/TPA-induced papillomas and nevi in the skin of mice selectively lacking retinoid-X-receptor alpha in epidermal keratinocytes, J. Invest. Dermatol., 2007, 127, 1250–1260.

    Article  CAS  PubMed  Google Scholar 

  28. T. I. Ellison, M. K. Smith, A. C. Gilliam and P. N. Macdonald, Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis, J. Invest. Dermatol., 2008, 128, 2508–2517.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. A. E. Teichert, H. Elalieh, P. M. Elias, J. Welsh and D. D. Bikle, Overexpression of hedgehog signaling is associated with epidermal tumor formation in vitamin D receptor-null mice, J. Invest. Dermatol., 2011, 131, 2289–2297.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. L. Daya-Grosjean and A. Sarasin, The role of UV induced lesions in skin carcinogenesis: an overview of oncogene and tumor suppressor gene modifications in xeroderma pigmentosum skin tumors, Mutat. Res., Fundam. Mol. Mech. Mutagen., 2005, 571, 43–56.

    Article  CAS  Google Scholar 

  31. M. Aszterbaum, A. Rothman, R. L. Johnson, M. Fisher, J. Xie, J. M. Bonifas, X. Zhang, M. P. Scott, E. H. Epstein Jr., Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome, J. Invest. Dermatol., 1998, 110, 885–888.

    Article  CAS  PubMed  Google Scholar 

  32. X. L. Ping, D. Ratner, H. Zhang, X. L. Wu, M. J. Zhang, F. F. Chen, D. N. Silvers, M. Peacocke and H. C. Tsou, PTCH mutations in squamous cell carcinoma of the skin, J. Invest. Dermatol., 2011, 116, 614–616.

    Article  Google Scholar 

  33. D. D. Bikle, Vitamin D and the skin: physiology and pathophysiology, Rev. Endocr. Metab. Disord., 2012, 13, 3–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. S. Pillai and D. D. Bikle, Role of intracellular-free calcium in the cornified envelope formation of keratinocytes: differences in the mode of action of extracellular calcium and 1,25 dihydroxyvitamin D3, J. Cell. Physiol., 1991, 146, 94–100.

    Article  CAS  PubMed  Google Scholar 

  35. D. D. Bikle, S. Pillai and E. Gee, Squamous carcinoma cell lines produce 1,25 dihydroxyvitamin D, but fail to respond to its prodifferentiating effect, J. Invest. Dermatol., 1991, 97, 435–441.

    Article  CAS  PubMed  Google Scholar 

  36. J. Hosomi, J. Hosoi, E. Abe, T. Suda and T. Kuroki, Regulation of terminal differentiation of cultured mouse epidermal cells by 1-alpha,25-dihydroxyvitamin D3, Endocrinology, 1983, 113, 1950–1957.

    Article  CAS  PubMed  Google Scholar 

  37. E. L. Smith, N. C. Walworth and M. F. Holick, Effect of 1-alpha,25-dihydroxyvitamin D3 on the morphologic and biochemical differentiation of cultured human epidermal keratinocytes grown in serum-free conditions, J. Invest. Dermatol., 1986, 86, 709–714.

    Article  CAS  PubMed  Google Scholar 

  38. J. A. McLane, M. Katz and N. Abdelkader, Effect of 1,25-dihydroxyvitamin D3 on human keratinocytes grown under different culture conditions, In Vitro Cell. Dev. Biol., 1990, 26, 379–387.

    Article  CAS  PubMed  Google Scholar 

  39. N. P. Hawker, S. D. Pennypacker, S. M. Chang and D. D. Bikle, Regulation of human epidermal keratinocyte differentiation by the vitamin D receptor and its coactivators DRIP205, SRC2, and SRC3, J. Invest. Dermatol., 2007, 127, 874.

    Article  CAS  PubMed  Google Scholar 

  40. C. L. Tu, W. Chang, Z. Xie and D. D. Bikle, Inactivation of the calcium sensing receptor inhibits E-cadherin-mediated cell-cell adhesion and calcium-induced differentiation in human epidermal keratinocytes, J. Biol. Chem., 2008, 283, 3519–3528.

    Article  CAS  PubMed  Google Scholar 

  41. C. L. Tu, Y. Oda, L. Komuves and D. D. Bikle, The role of the calcium-sensing receptor in epidermal differentiation, Cell Calcium, 2004, 35, 265–273.

    Article  CAS  PubMed  Google Scholar 

  42. Z. Xie and D. D. Bikle, Cloning of the human phospholipase C-gamma1 promoter and identification of a DR6-type vitamin D-responsive element, J. Biol. Chem., 1997, 272, 6573–6577.

    Article  CAS  PubMed  Google Scholar 

  43. Z. Xie and D. D. Bikle, Phospholipase C-gamma1 is required for calcium-induced keratinocyte differentiation, J. Biol. Chem., 1999, 274, 20421–20424.

    Article  CAS  PubMed  Google Scholar 

  44. Z. Xie and D. D. Bikle, Inhibition of 1,25-dihydroxyvitamin-D-induced keratinocyte differentiation by blocking the expression of phospholipase C-gamma1, J. Invest. Dermatol., 2001, 117, 1250–1254.

    Article  CAS  PubMed  Google Scholar 

  45. K. Matsumoto, K. Hashimoto, Y. Nishida, M. Hashiro and K. Yoshikawa, Growth-inhibitory effects of 1,25-dihydroxyvitamin D3 on normal human keratinocytes cultured in serum-free medium, Biochem. Biophys. Res. Commun., 1990, 166, 916–923.

    Article  CAS  PubMed  Google Scholar 

  46. D. D. Bikle, The vitamin D receptor: a tumor suppressor in skin, Discov. Med., 2011, 11, 7–17.

    PubMed  PubMed Central  Google Scholar 

  47. Y. Oda, Y. Uchida, S. Moradian, D. Crumrine, P. Elias and D. Bikle, Vitamin D receptor and coactivators SRC 2 and 3 regulate epidermis-specific sphingolipid production and permeability barrier formation, J. Invest. Dermatol., 2009, 129, 1367–1378.

    Article  CAS  PubMed  Google Scholar 

  48. J. Schauber, R. A. Dorschner, A. B. Coda, A. S. Buchau, P. T. Liu, D. Kiken, Y. R. Helfrich, S. Kang, H. Z. Elalieh, A. Steinmeyer, U. Zugel, D. D. Bikle, R. L. Modlin and R. L. Gallo, Injury enhances TLR2 function and antimicrobial peptide expression through a vitamin D-dependent mechanism, J. Clin. Invest., 2007, 117, 803–811.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. J. Schauber, R. A. Dorschner, K. Yamasaki, B. Brouha and R. L. Gallo, Control of the innate epithelial antimicrobial response is cell-type specific and dependent on relevant microenvironmental stimuli, Immunology, 2006, 118, 509–519.

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Y. C. Li, A. E. Pirro, M. Amling, G. Delling, R. Baron, R. Bronson and M. B. Demay, Targeted ablation of the vitamin D receptor: an animal model of vitamin D-dependent rickets type II with alopecia, Proc. Natl. Acad. Sci. U. S. A., 1997, 94, 9831–9835.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. T. Yoshizawa, Y. Handa, Y. Uematsu, S. Takeda, K. Sekine, Y. Yoshihara, T. Kawakami, K. Arioka, H. Sato, Y. Uchiyama, S. Masushige, A. Fukamizu, T. Matsumoto and S. Kato, Mice lacking the vitamin D receptor exhibit impaired bone formation, uterine hypoplasia and growth retardation after weaning, Nat. Genet., 1997, 16, 391–396.

    Article  CAS  PubMed  Google Scholar 

  52. P. J. Malloy, J. W. Pike and D. Feldman, The vitamin D receptor and the syndrome of hereditary 1,25-dihydroxyvitamin D-resistant rickets, Endocr. Rev., 1999, 20, 156–188.

    CAS  PubMed  Google Scholar 

  53. Z. Xie, L. Komuves, Q. C. Yu, H. Elalieh, D. C. Ng, C. Leary, S. Chang, D. Crumrine, T. Yoshizawa, S. Kato and D. D. Bikle, Lack of the vitamin D receptor is associated with reduced epidermal differentiation and hair follicle growth, J. Invest. Dermatol., 2002, 118, 11–16.

    Article  CAS  PubMed  Google Scholar 

  54. D. D. Bikle, H. Elalieh, S. Chang, Z. Xie and J. P. Sundberg, Development and progression of alopecia in the vitamin D receptor null mouse, J. Cell. Physiol., 2006, 207, 340–353.

    Article  CAS  PubMed  Google Scholar 

  55. D. D. Bikle, S. Chang, D. Crumrine, H. Elalieh, M. Q. Man, E. H. Choi, O. Dardenne, Z. Xie, R. S. Arnaud, K. Feingold and P. M. Elias, 25 Hydroxyvitamin D 1 alpha-hydroxylase is required for optimal epidermal differentiation and permeability barrier homeostasis, J. Invest. Dermatol., 2004, 122, 984–992.

    Article  CAS  PubMed  Google Scholar 

  56. B. Muehleisen, D. D. Bikle, C. Aguilera, D. W. Burton, G. L. Sen, L. J. Deftos and R. L. Gallo, PTH/PTHrP and vitamin D control antimicrobial peptide expression and susceptibility to bacterial skin infection, Sci. Transl. Med., 2012, 4, 135ra166.

    Article  CAS  Google Scholar 

  57. P. C. Barnfield, X. Zhang, V. Thanabalasingham, M. Yoshida and C. C. Hui, Negative regulation of Gli1 and Gli2 activator function by suppressor of fused through multiple mechanisms, Differentiation, 2005, 73, 397–405.

    Article  CAS  PubMed  Google Scholar 

  58. J. Svard, K. Heby-Henricson, M. Persson-Lek, B. Rozell, M. Lauth, A. Bergstrom, J. Ericson, R. Toftgard and S. Teglund, Genetic elimination of Suppressor of fused reveals an essential repressor function in the mammalian Hedgehog signaling pathway, Dev. Cell, 2006, 10, 187–197.

    Article  PubMed  CAS  Google Scholar 

  59. G. Regl, M. Kasper, H. Schnidar, T. Eichberger, G. W. Neill, M. S. Ikram, A. G. Quinn, M. P. Philpott, A. M. Frischauf and F. Aberger, The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells, Oncogene, 2004, 23, 1263–1274.

    Article  CAS  PubMed  Google Scholar 

  60. G. Regl, M. Kasper, H. Schnidar, T. Eichberger, G. W. Neill, M. P. Philpott, H. Esterbauer, C. Hauser-Kronberger, A. M. Frischauf and F. Aberger, Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2, Cancer Res., 2004, 64, 7724–7731.

    Article  CAS  PubMed  Google Scholar 

  61. G. Regl, G. W. Neill, T. Eichberger, M. Kasper, M. S. Ikram, J. Koller, H. Hintner, A. G. Quinn, A. M. Frischauf and F. Aberger, Human GLI2 and GLI1 are part of a positive feedback mechanism in basal cell carcinoma, Oncogene, 2002, 21, 5529–5539.

    Article  CAS  PubMed  Google Scholar 

  62. M. Grachtchouk, R. Mo, S. Yu, X. Zhang, H. Sasaki, C. C. Hui and A. A. Dlugosz, Basal cell carcinomas in mice overexpressing Gli2 in skin, Nat. Genet., 2000, 24, 216–217.

    Article  CAS  PubMed  Google Scholar 

  63. M. Nilsson, A. B. Unden, D. Krause, U. Malmqwist, K. Raza, P. G. Zaphiropoulos and R. Toftgard, Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1, Proc. Natl. Acad. Sci. U. S. A., 2000, 97, 3438–3443.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. H. Hahn, C. Wicking, P. G. Zaphiropoulous, M. R. Gailani, S. Shanley, A. Chidambaram, I. Vorechovsky, E. Holmberg, A. B. Unden, S. Gillies, K. Negus, I. Smyth, C. Pressman, D. J. Leffell, B. Gerrard, A. M. Goldstein, M. Dean, R. Toftgard, G. Chenevix-Trench, B. Wainwright and A. E. Bale, Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome, Cell, 1996, 85, 841–851.

    Article  CAS  PubMed  Google Scholar 

  65. A. Uhmann, H. Niemann, B. Lammering, C. Henkel, I. Hess, F. Nitzki, A. Fritsch, N. Prufer, A. Rosenberger, C. Dullin, A. Schraepler, J. Reifenberger, S. Schweyer, T. Pietsch, F. Strutz, W. Schulz-Schaeffer and H. Hahn, Antitumoral effects of calcitriol in basal cell carcinomas involve inhibition of hedgehog signaling and induction of vitamin D receptor signaling and differentiation, Mol. Cancer Ther., 2012, 10, 2179–2188.

    Article  CAS  Google Scholar 

  66. H. F. Luderer, F. Gori and M. B. Demay, Lymphoid enhancer-binding factor-1 (LEF1) interacts with the DNA-binding domain of the vitamin D receptor, J. Biol. Chem., 2011, 286, 18444–18451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. M. F. Bijlsma, C. A. Spek, D. Zivkovic, S. van de Water, F. Rezaee and M. P. Peppelenbosch, Repression of smoothened by patched-dependent (pro-)vitamin D3 secretion, PLoS Biol., 2006, 4, e232.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  68. J. Y. Tang, T. Z. Xiao, Y. Oda, K. S. Chang, E. Shpall, A. Wu, P. L. So, J. Hebert, D. Bikle, E. H. Epstein Jr., Vitamin D3 inhibits hedgehog signaling and proliferation in murine basal cell carcinomas, Cancer Prev. Res., 2011, 4, 744–751.

    Article  CAS  Google Scholar 

  69. T. C. He, A. B. Sparks, C. Rago, H. Hermeking, L. Zawel, L. T. da Costa, P. J. Morin, B. Vogelstein and K. W. Kinzler, Identification of c-MYC as a target of the APC pathway, Science., 1998, 281, 1509–1512.

    Article  CAS  PubMed  Google Scholar 

  70. Z. Xie and D. D. Bikle, The recruitment of phosphatidylinositol 3-kinase to the E-cadherin-catenin complex at the plasma membrane is required for calcium-induced phospholipase C-gamma1 activation and human keratinocyte differentiation, J. Biol. Chem., 2007, 282, 8695–8703.

    Article  CAS  PubMed  Google Scholar 

  71. M. Bienz, Beta-Catenin: a pivot between cell adhesion and Wnt signalling, Curr. Biol., 2005, 15, R64–R67.

    Article  CAS  PubMed  Google Scholar 

  72. E. F. Chan, U. Gat, J. M. McNiff and E. Fuchs, A common human skin tumour is caused by activating mutations in beta-catenin, Nat. Genet., 1999, 21, 410–413.

    Article  CAS  PubMed  Google Scholar 

  73. U. Gat, R. DasGupta, L. Degenstein and E. Fuchs, De Novo hair follicle morphogenesis and hair tumors in mice expressing a truncated beta-catenin in skin, Cell, 1998, 95, 605–614.

    Article  CAS  PubMed  Google Scholar 

  74. J. Xia, K. Urabe, Y. Moroi, T. Koga, H. Duan, Y. Li and M. Furue, Beta-Catenin mutation and its nuclear localization are confirmed to be frequent causes of Wnt signaling pathway activation in pilomatricomas, J. Dermatol. Sci., 2006, 41, 67–75.

    Article  CAS  PubMed  Google Scholar 

  75. H. G. Palmer, J. M. Gonzalez-Sancho, J. Espada, M. T. Berciano, I. Puig, J. Baulida, M. Quintanilla, A. Cano, A. G. de Herreros, M. Lafarga and A. Munoz, Vitamin D(3) promotes the differentiation of colon carcinoma cells by the induction of E-cadherin and the inhibition of beta-catenin signaling, J. Cell Biol., 2001, 154, 369–387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. S. Shah, A. Hecht, R. Pestell and S. W. Byers, Trans-repression of beta-catenin activity by nuclear receptors, J. Biol. Chem., 2003, 278, 48137–48145.

    Article  CAS  PubMed  Google Scholar 

  77. S. Shah, M. N. Islam, S. Dakshanamurthy, I. Rizvi, M. Rao, R. Herrell, G. Zinser, M. Valrance, A. Aranda, D. Moras, A. Norman, J. Welsh and S. W. Byers, The molecular basis of vitamin D receptor and beta-catenin crossregulation, Mol. Cell, 2006, 21, 799–809.

    Article  PubMed  CAS  Google Scholar 

  78. H. G. Palmer, F. Anjos-Afonso, G. Carmeliet, H. Takeda and F. M. Watt, The vitamin D receptor is a wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis, PLoS One, 2008, 3, e1483.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  79. L. Cianferotti, M. Cox, K. Skorija and M. B. Demay, Vitamin D receptor is essential for normal keratinocyte stem cell function, Proc. Natl. Acad. Sci. U. S. A., 2007, 104, 9428–9433.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. H. Sigmundsdottir, J. Pan, G. F. Debes, C. Alt, A. Habtezion, D. Soler and E. C. Butcher, DCs metabolize sunlight-induced vitamin D3 to ‘program’ T cell attraction to the epidermal chemokine CCL27, Nat. Immunol., 2007, 8, 285–293.

    Article  CAS  PubMed  Google Scholar 

  81. S. Chen, G. P. Sims, X. X. Chen, Y. Y. Gu, S. Chen and P. E. Lipsky, Modulatory effects of 1,25-dihydroxyvitamin D3 on human B cell differentiation, J. Immunol., 2007, 179, 1634–1647.

    Article  CAS  PubMed  Google Scholar 

  82. D. Bikle, Vitamin D and immune function: understanding common pathways, Curr. Osteoporosis Rep., 2009, 7, 58–63.

    Article  Google Scholar 

  83. W. F. Rigby, T. Stacy and M. W. Fanger, Inhibition of T lymphocyte mitogenesis by 1,25-dihydroxyvitamin D3 (calcitriol), J. Clin. Invest., 1984, 74, 1451–1455.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. J. M. Lemire, D. C. Archer, L. Beck and H. L. Spiegelberg, Immunosuppressive actions of 1,25-dihydroxyvitamin D3: preferential inhibition of Th1 functions, J. Nutr., 1995, 125, 1704S–1708S.

    CAS  PubMed  Google Scholar 

  85. C. Daniel, N. A. Sartory, N. Zahn, H. H. Radeke and J. M. Stein, Immune modulatory treatment of trinitrobenzene sulfonic acid colitis with calcitriol is associated with a change of a T helper (Th) 1/Th17 to a Th2 and regulatory T cell profile, J. Pharmacol. Exp. Ther., 2008, 324, 23–33.

    Article  CAS  PubMed  Google Scholar 

  86. E. Bettelli, T. Korn, M. Oukka and V. K. Kuchroo, Induction and effector functions of T(H)17 cells, Nature, 2008, 453, 1051–1057.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  87. A. Boonstra, F. J. Barrat, C. Crain, V. L. Heath, H. F. Savelkoul, A. O’Garra, 1 alpha,25-Dihydroxyvitamin d3 has a direct effect on naive CD4(+) T cells to enhance the development of Th2 cells, J. Immunol., 2001, 167, 4974–4980.

    Article  CAS  PubMed  Google Scholar 

  88. G. Penna and L. Adorini, 1 alpha,25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation, J. Immunol., 2000, 164, 2405–2411.

    Article  CAS  PubMed  Google Scholar 

  89. M. D. Griffin, N. Xing and R. Kumar, Vitamin D and its analogs as regulators of immune activation and antigen presentation, Annu. Rev. Nutr., 2003, 23, 117–145.

    Article  CAS  PubMed  Google Scholar 

  90. L. Adorini, Intervention in autoimmunity: the potential of vitamin D receptor agonists, Cell. Immunol., 2005, 233, 115–124.

    Article  CAS  PubMed  Google Scholar 

  91. L. Adorini, S. Amuchastegui and K. C. Daniel, Prevention of chronic allograft rejection by Vitamin D receptor agonists, Immunol. Lett., 2005, 100, 34–41.

    Article  CAS  PubMed  Google Scholar 

  92. P. T. Liu, S. R. Krutzik and R. L. Modlin, Therapeutic implications of the TLR and VDR partnership, Trends Mol. Med., 2007, 13, 117–124.

    Article  PubMed  CAS  Google Scholar 

  93. R. Medzhitov, Recognition of microorganisms and activation of the immune response, Nature, 2007, 449, 819–826.

    Article  CAS  PubMed  Google Scholar 

  94. A. F. Gombart, N. Borregaard and H. P. Koeffler, Human cathelicidin antimicrobial peptide (CAMP) gene is a direct target of the vitamin D receptor and is strongly up-regulated in myeloid cells by 1,25-dihydroxyvitamin D3, FASEB J., 2005, 19, 1067–1077.

    Article  CAS  PubMed  Google Scholar 

  95. T. T. Wang, F. P. Nestel, V. Bourdeau, Y. Nagai, Q. Wang, J. Liao, L. Tavera-Mendoza, R. Lin, J. W. Hanrahan, S. Mader and J. H. White, Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression, J. Immunol., 2004, 173, 2909–2912.

    Article  CAS  PubMed  Google Scholar 

  96. P. T. Liu, S. Stenger, H. Li, L. Wenzel, B. H. Tan, S. R. Krutzik, M. T. Ochoa, J. Schauber, K. Wu, C. Meinken, D. L. Kamen, M. Wagner, R. Bals, A. Steinmeyer, U. Zugel, R. L. Gallo, D. Eisenberg, M. Hewison, B. W. Hollis, J. S. Adams, B. R. Bloom and R. L. Modlin, Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response, Science, 2006, 311, 1770–1773.

    Article  CAS  PubMed  Google Scholar 

  97. M. L. Kripke, C. G. Munn, A. Jeevan, J. M. Tang and C. Bucana, Evidence that cutaneous antigen-presenting cells migrate to regional lymph nodes during contact sensitization, J. Immunol., 1990, 145, 2833–2838.

    CAS  PubMed  Google Scholar 

  98. Y. Matsumura and H. N. Ananthaswamy, Toxic effects of ultraviolet radiation on the skin, Toxicol. Appl. Pharmacol., 2004, 195, 298–308.

    Article  CAS  PubMed  Google Scholar 

  99. G. B. Toews, P. R. Bergstresser and J. W. Streilein, Epidermal Langerhans cell density determines whether contact hypersensitivity or unresponsiveness follows skin painting with DNFB, J. Immunol., 1980, 124, 445–453.

    CAS  PubMed  Google Scholar 

  100. J. C. Simon, P. D. Cruz Jr., R. E. Tigelaar, R. D. Sontheimer and P. R. Bergstresser, Adhesion molecules CD11a, CD18, and ICAM-1 on human epidermal Langerhans cells serve a functional role in the activation of alloreactive T cells, J. Invest. Dermatol., 1991, 96, 148–151.

    Article  CAS  PubMed  Google Scholar 

  101. A. Tang and M. C. Udey, Inhibition of epidermal Langerhans cell function by low dose ultraviolet B radiation. Ultraviolet B radiation selectively modulates ICAM-1 (CD54) expression by murine Langerhans cells, J. Immunol., 1991, 146, 3347–3355.

    CAS  PubMed  Google Scholar 

  102. R. Glaser, F. Navid, W. Schuller, C. Jantschitsch, J. Harder, J. M. Schroder, A. Schwarz and T. Schwarz, UV-B radiation induces the expression of antimicrobial peptides in human keratinocytes in vitro and in vivo, J. Allergy Clin. Immunol., 2009, 123, 1117–1123.

    Article  PubMed  CAS  Google Scholar 

  103. L. Mallbris, D. W. Edstrom, L. Sundblad, F. Granath and M. Stahle, UVB upregulates the antimicrobial protein hCAP18 mRNA in human skin, J. Invest. Dermatol., 2005, 125, 1072–1074.

    Article  CAS  PubMed  Google Scholar 

  104. M. L. Kripke and M. S. Fisher, Immunologic parameters of ultraviolet carcinogenesis, J. Natl. Cancer Inst.., 1976, 57, 211–215.

    Article  CAS  PubMed  Google Scholar 

  105. K. M. Dixon, S. S. Deo, A. W. Norman, J. E. Bishop, G. M. Halliday, V. E. Reeve and R. S. Mason, In vivo relevance for photoprotection by the vitamin D rapid response pathway, J. Steroid Biochem. Mol. Biol., 2007, 103, 451–456.

    Article  CAS  PubMed  Google Scholar 

  106. D. L. Damian, Y. J. Kim, K. M. Dixon, G. M. Halliday, A. Javeri and R. S. Mason, Topical calcitriol protects from UV-induced genetic damage but suppresses cutaneous immunity in humans, Exp. Dermatol., 2010, 19, e23–e30.

    Article  PubMed  Google Scholar 

  107. S. E. Freeman, H. Hacham, R. W. Gange, D. J. Maytum, J. C. Sutherland and B. M. Sutherland, Wavelength dependence of pyrimidine dimer formation in DNA of human skin irradiated in situ with ultraviolet light, Proc. Natl. Acad. Sci. U. S. A., 1989, 86, 5605–5609.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. M. R. Hussein, Ultraviolet radiation and skin cancer: molecular mechanisms, J. Cutaneous Pathol., 2005, 32, 191–205.

    Article  Google Scholar 

  109. A. Ziegler, D. J. Leffell, S. Kunala, H. W. Sharma, M. Gailani, J. A. Simon, A. J. Halperin, H. P. Baden, P. E. Shapiro and A. E. Bale, et al., Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers, Proc. Natl. Acad. Sci. U. S. A., 1993, 90, 4216–4220.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. A. Ziegler, A. S. Jonason, D. J. Leffell, J. A. Simon, H. W. Sharma, J. Kimmelman, L. Remington, T. Jacks and D. E. Brash, Sunburn and p53 in the onset of skin cancer, Nature, 1994, 372, 773–776.

    Article  CAS  PubMed  Google Scholar 

  111. D. E. Brash, J. A. Rudolph, J. A. Simon, A. Lin, G. J. McKenna, H. P. Baden, A. J. Halperin and J. Ponten, A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma, Proc. Natl. Acad. Sci. U. S. A., 1991, 88, 10124–10128.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. T. Bito, M. Ueda, N. U. Ahmed, T. Nagano and M. Ichihashi, Cyclin D and retinoblastoma gene product expression in actinic keratosis and cutaneous squamous cell carcinoma in relation to p53 expression, J. Cutaneous Pathol., 1995, 22, 427–434.

    Article  CAS  Google Scholar 

  113. G. Li, D. L. Mitchell, V. C. Ho, J. C. Reed and V. A. Tron, Decreased DNA repair but normal apoptosis in ultraviolet-irradiated skin of p53-transgenic mice, Am. J. Pathol., 1996, 148, 1113–1123.

    CAS  PubMed  PubMed Central  Google Scholar 

  114. T. D. Tlsty, B. H. Margolin and K. Lum, Differences in the rates of gene amplification in nontumorigenic and tumorigenic cell lines as measured by Luria–Delbruck fluctuation analysis, Proc. Natl. Acad. Sci. U. S. A., 1989, 86, 9441–9445.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. T. D. Tlsty, Normal diploid human and rodent cells lack a detectable frequency of gene amplification, Proc. Natl. Acad. Sci. U. S. A., 1990, 87, 3132–3136.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. V. M. Maher, D. J. Dorney, A. L. Mendrala, B. Konze-Thomas and J. J. McCormick, DNA excision-repair processes in human cells can eliminate the cytotoxic and mutagenic consequences of ultraviolet irradiation, Mutat. Res., Fundam. Mol. Mech. Mutagen., 1979, 62, 311–323.

    Article  CAS  Google Scholar 

  117. J. Bartkova, N. Rezaei, M. Liontos, P. Karakaidos, D. Kletsas, N. Issaeva, L. V. Vassiliou, E. Kolettas, K. Niforou, V. C. Zoumpourlis, M. Takaoka, H. Nakagawa, F. Tort, K. Fugger, F. Johansson, M. Sehested, C. L. Andersen, L. Dyrskjot, T. Orntoft, J. Lukas, C. Kittas, T. Helleday, T. D. Halazonetis, J. Bartek and V. G. Gorgoulis, Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints, Nature, 2006, 444, 633–637.

    Article  CAS  PubMed  Google Scholar 

  118. J. H. Bielas, K. R. Loeb, B. P. Rubin, L. D. True and L. A. Loeb, Human cancers express a mutator phenotype, Proc. Natl. Acad. Sci. U. S. A., 2006, 103, 18238–18242.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  119. R. H. Chen, V. M. Maher and J. J. McCormick, Effect of excision repair by diploid human fibroblasts on the kinds and locations of mutations induced by (+/−)-7-beta,8-alpha-dihydroxy-9 alpha,10 alpha-epoxy-7,8,9,10- tetrahydrobenzo[a]pyrene in the coding region of the HPRT gene, Proc. Natl. Acad. Sci. U. S. A., 1990, 87, 8680–8684.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. R. D. Wood, DNA damage recognition during nucleotide excision repair in mammalian cells, Biochimie, 1999, 81, 39–44.

    Article  CAS  PubMed  Google Scholar 

  121. S. Sertic, S. Pizzi, F. Lazzaro, P. Plevani, M. Muzi-Falconi, NER and DDR: classical music with new instruments, Cell Cycle, 2012, 11, 668–674.

    Article  CAS  PubMed  Google Scholar 

  122. I. Mellon, V. A. Bohr, C. A. Smith and P. C. Hanawalt, Preferential DNA repair of an active gene in human cells, Proc. Natl. Acad. Sci. U. S. A., 1986, 83, 8878–8882.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  123. I. Mellon, G. Spivak and P. C. Hanawalt, Selective removal of transcription-blocking DNA damage from the transcribed strand of the mammalian DHFR gene, Cell, 1987, 51, 241–249.

    Article  CAS  PubMed  Google Scholar 

  124. I. Mellon, D. K. Rajpal, M. Koi, C. R. Boland and G. N. Champe, Transcription-coupled repair deficiency and mutations in human mismatch repair genes, Science, 1996, 272, 557–560.

    Article  CAS  PubMed  Google Scholar 

  125. V. A. Bohr, Gene specific DNA repair, Carcinogenesis, 1991, 12, 1983–1992.

    Article  CAS  PubMed  Google Scholar 

  126. P. C. Hanawalt, Transcription-coupled repair and human disease, Science, 1994, 266, 1957–1958.

    Article  CAS  PubMed  Google Scholar 

  127. J. H. Hoeijmakers, Genome maintenance mechanisms for preventing cancer, Nature, 2001, 411, 366–374.

    Article  CAS  PubMed  Google Scholar 

  128. R. D. Wood, M. Mitchell, J. Sgouros and T. Lindahl, Human DNA repair genes, Science, 2001, 291, 1284–1289.

    Article  CAS  PubMed  Google Scholar 

  129. S. K. Demetriou, K. Ona-Vu, A. E. Teichert, J. E. Cleaver, D. D. Bikle and D. H. Oh, Vitamin D receptor mediates DNA repair and is UV inducible in intact epidermis but not in cultured keratinocytes, J. Invest. Dermatol., 2012, 132, 2097–2100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. K. M. Dixon, S. S. Deo, G. Wong, M. Slater, A. W. Norman, J. E. Bishop, G. H. Posner, S. Ishizuka, G. M. Halliday, V. E. Reeve and R. S. Mason, Skin cancer prevention: a possible role of 1,25dihydroxyvitamin D3 and its analogs, J. Steroid Biochem. Mol. Biol., 2005, 97, 137–143.

    Article  CAS  PubMed  Google Scholar 

  131. R. Gupta, K. M. Dixon, S. S. Deo, C. J. Holliday, M. Slater, G. M. Halliday, V. E. Reeve and R. S. Mason, Photoprotection by 1,25 dihydroxyvitamin D3 is associated with an increase in p53 and a decrease in nitric oxide products, J. Invest. Dermatol., 2007, 127, 707–715.

    Article  CAS  PubMed  Google Scholar 

  132. P. R. Moll, V. Sander, A. M. Frischauf and K. Richter, Expression profiling of vitamin D treated primary human keratinocytes, J. Cell. Biochem., 2007, 100, 574–592.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Departments of Medicine and Dermatology, San Francisco VA Medical Center and University of California, San Francisco, CA, USA

    Daniel D. Bikle

Authors
  1. Daniel D. Bikle
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel D. Bikle.

Additional information

Contribution to the Vitamin D update collected papers.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bikle, D.D. Protective actions of vitamin D in UVB induced skin cancer. Photochem Photobiol Sci 11, 1808–1816 (2012). https://doi.org/10.1039/c2pp25251a

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1039/c2pp25251a

Search

Navigation