Voltar
Carta Acesso aberto Revisado por pares
BIBTEX RIS

Vitamin D Receptor, UVR, and Skin Cancer: A Potential Protective Mechanism

2008; Elsevier BV; Volume: 128; Issue: 10 Linguagem: Inglês

10.1038/jid.2008.249

ISSN

1523-1747

Autores

Daniel D. Bikle,

Tópico(s)

Cancer-related Molecular Pathways

Resumo

More than 1 million skin cancers occur annually in the United States—of which 80% are basal-cell carcinoma (BCC), 16% are squamous-cell carcinoma (SCC), and 4% are melanomas—making skin cancer by far the most common cancer (Greenlee et al., 2001Greenlee R.T. Hill-Harmon M.B. Murray T. Thun M. Cancer statistics, 2001.CA Cancer J Clin. 2001; 51: 15-36Crossref PubMed Scopus (3257) Google Scholar). UVR is the major etiologic agent. UV wavelengths shorter than 280 nm (UVC) are absorbed by the ozone layer and do not reach the earth. UV wavelengths longer than 320 nm (UVA) have limited ability to induce the characteristic mutations in DNA seen in epidermal cancers. Thus, UVB, with a spectrum between 280 and 320 nm, is the major cause of these cancers (Freeman et al., 1989Freeman S.E. Hacham H. Gange R.W. Maytum D.J. Sutherland J.C. Sutherland B.M. Wavelength dependence of pyrimidine dimer formation in DNA of human skin irradiated in situ with ultraviolet light.Proc Natl Acad Sci USA. 1989; 86: 5605-5609Crossref PubMed Scopus (252) Google Scholar), but this is the same spectrum required for vitamin D production in the skin. Is there a link? More than 1 million skin cancers occur annually in the United States—of which 80% are basal-cell carcinoma (BCC), 16% are squamous-cell carcinoma (SCC), and 4% are melanomas—making skin cancer by far the most common cancer (Greenlee et al., 2001Greenlee R.T. Hill-Harmon M.B. Murray T. Thun M. Cancer statistics, 2001.CA Cancer J Clin. 2001; 51: 15-36Crossref PubMed Scopus (3257) Google Scholar). UVR is the major etiologic agent. UV wavelengths shorter than 280 nm (UVC) are absorbed by the ozone layer and do not reach the earth. UV wavelengths longer than 320 nm (UVA) have limited ability to induce the characteristic mutations in DNA seen in epidermal cancers. Thus, UVB, with a spectrum between 280 and 320 nm, is the major cause of these cancers (Freeman et al., 1989Freeman S.E. Hacham H. Gange R.W. Maytum D.J. Sutherland J.C. Sutherland B.M. Wavelength dependence of pyrimidine dimer formation in DNA of human skin irradiated in situ with ultraviolet light.Proc Natl Acad Sci USA. 1989; 86: 5605-5609Crossref PubMed Scopus (252) Google Scholar), but this is the same spectrum required for vitamin D production in the skin. Is there a link? The principal genotoxic lesions induced by UVR are cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts, which, if not repaired, result in C-to-T or CC-to-TT mutations, the UVB "signature" lesion (Hussein, 2005Hussein M.R. Ultraviolet radiation and skin cancer: molecular mechanisms.J Cutan Pathol. 2005; 32: 191-205Crossref PubMed Scopus (208) Google Scholar). Mutations in p53 are common (50–90%) in both BCC and SCC (Brash et al., 1991Brash D.E. Rudolph J.A. Simon J.A. Lin A. McKenna G.J. Baden H.P. et al.A role for sunlight in skin cancer: UV-induced p53 mutations in squamous cell carcinoma.Proc Natl Acad Sci USA. 1991; 88: 10124-10128Crossref PubMed Scopus (1642) Google Scholar; Ziegler et al., 1993Ziegler A. Leffell D.J. Kunala S. Sharma H.W. Gailani M. Simon J.A. et al.Mutation hotspots due to sunlight in the p53 gene of nonmelanoma skin cancers.Proc Natl Acad Sci USA. 1993; 90: 4216-4220Crossref PubMed Scopus (642) Google Scholar, Ziegler et al., 1994Ziegler A. Jonason A.S. Leffell D.J. Simon J.A. Sharma H.W. Kimmelman J. et al.Sunburn and p53 in the onset of skin cancer.Nature. 1994; 372: 773-776Crossref PubMed Scopus (1299) Google Scholar; Daya-Grosjean and Sarasin, 2005Daya-Grosjean L. Sarasin A. 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. 2005; 571: 43-56Crossref PubMed Scopus (107) Google Scholar), as well as in actinic keratoses, the precursor lesions to SCC (Bito et al., 1995Bito T. Ueda M. Ahmed N.U. Nagano T. Ichihashi M. Cyclin D and retinoblastoma gene product expression in actinic keratosis and cutaneous squamous cell carcinoma in relation to p53 expression.J Cutan Pathol. 1995; 22: 427-434Crossref PubMed Scopus (42) Google Scholar). Precursor lesions for BCC have not been identified, but BCCs are thought to arise from interfollicular basal cells, hair follicles, and sebaceous glands. Mutations in ras are much more common in SCC than in BCC (Reifenberger et al., 2005Reifenberger J. Wolter M. Knobbe C.B. Kohler B. Schonicke A. Scharwachter C. et al.Somatic mutations in the PTCH, SMOH, SUFUH and TP53 genes in sporadic basal cell carcinomas.Br J Dermatol. 2005; 152: 43-51Crossref PubMed Scopus (299) Google Scholar), whereas mutations in the hedgehog (Hh) signaling pathway—in particular, in patched 1 (Ptch1)—characterize BCC (Hahn et al., 1996Hahn H. Wicking C. Zaphiropoulous P.G. Gailani M.R. Shanley S. Chidambaram A. et al.Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.Cell. 1996; 85: 841-851Abstract Full Text Full Text PDF PubMed Scopus (1611) Google Scholar; Johnson et al., 1996Johnson R.L. Rothman A.L. Xie J. Goodrich L.V. Bare J.W. Bonifas J.M. et al.Human homolog of patched, a candidate gene for the basal cell nevus syndrome.Science. 1996; 272: 1668-1671Crossref PubMed Scopus (1570) Google Scholar; Aszterbaum et al., 1998Aszterbaum M. Rothman A. Johnson R.L. Fisher M. Xie J. Bonifas J.M. et al.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: 885-888Crossref PubMed Scopus (239) Google Scholar, Aszterbaum et al., 1999Aszterbaum M. Epstein J. Oro A. Douglas V. LeBoit P.E. Scott M.P. et al.Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice.Nat Med. 1999; 5: 1285-1291Crossref PubMed Scopus (326) Google Scholar). However, loss of heterozygosity in the region including the Ptch1 gene has been reported in a high percentage of both BCCs and SCCs (Danaee et al., 2006Danaee H. Karagas M.R. Kelsey K.T. Perry A.E. Nelson H.H. Allelic loss at Drosophila patched gene is highly prevalent in basal and squamous cell carcinomas of the skin.J Invest Dermatol. 2006; 126: 1152-1158Abstract Full Text Full Text PDF PubMed Scopus (29) Google Scholar), and polymorphisms of the Ptch1 gene have altered the resistance to SCC formation in mice expressing an activated ras oncogene (Wakabayashi et al., 2007Wakabayashi Y. Mao J.H. Brown K. Girardi M. Balmain A. Promotion of Hras-induced squamous carcinomas by a polymorphic variant of the Patched gene in FVB mice.Nature. 2007; 445: 761-765Crossref PubMed Scopus (87) Google Scholar). Thus, alterations in the Hh signaling pathway contribute to the formation of both SCC and BCC. 1,25-Dihydroxyvitamin D3 (1,25(OH)2D3) has been evaluated for its potential anticancer activity for approximately 25 years (Eisman et al., 1979Eisman J.A. Martin T.J. MacIntyre I. Moseley J.M. 1,25-Dihydroxyvitamin-D-receptor in breast cancer cells.Lancet. 1979; 2: 1335-1336Abstract PubMed Scopus (147) Google Scholar). The list of malignant cells that express the receptor for 1,25(OH)2D3—vitamin D receptor (VDR)—is now quite extensive and for the purposes of this Commentary includes BCCs and SCCs (Ratnam et al., 1996Ratnam A.V. Cho J.K. Bikle D.D. 1,25-Dihydroxyvitamin D3 enhances the calcium response of keratinocytes.J Invest Dermatol. 1996; 106: 910Crossref Scopus (33) Google Scholar; Kamradt et al., 2003Kamradt J. Rafi L. Mitschele T. Meineke V. Gartner B.C. Wolfgang T. et al.Analysis of the vitamin D system in cutaneous malignancies.Recent Results Cancer Res. 2003; 164: 259-269Crossref PubMed Scopus (30) Google Scholar), as well as melanomas (Colston et al., 1981Colston K. Colston M.J. Feldman D. 1,25-Dihydroxyvitamin D3 and malignant melanoma: the presence of receptors and inhibition of cell growth in culture.Endocrinology. 1981; 108: 1083-1086Crossref PubMed Scopus (476) Google Scholar). The accepted basis for the promise of 1,25(OH)2D3 in the prevention and treatment of malignancy includes its antiproliferative, prodifferentiating effects on most cell types. Epidemiologic evidence supporting the importance of adequate vitamin D nutrition (including sunlight exposure) for the prevention of a number of cancers, including those of the colon, breast, and prostate (Garland et al., 1985Garland C. Shekelle R.B. Barrett-Connor E. Criqui M.H. Rossof A.H. Paul O. Dietary vitamin D and calcium and risk of colorectal cancer: a 19-year prospective study in men.Lancet. 1985; 1: 307-309Abstract PubMed Scopus (626) Google Scholar, Garland et al., 1990Garland F.C. Garland C.F. Gorham E.D. Young J.F. Geographic variation in breast cancer mortality in the United States: a hypothesis involving exposure to solar radiation.Prev Med. 1990; 19: 614-622Crossref PubMed Scopus (453) Google Scholar; Hanchette and Schwartz, 1992Hanchette C.L. Schwartz G.G. Geographic patterns of prostate cancer mortality. Evidence for a protective effect of ultraviolet radiation.Cancer. 1992; 70: 2861-2869Crossref PubMed Scopus (570) Google Scholar; Bostick et al., 1993Bostick R.M. Potter J.D. Sellers T.A. McKenzie D.R. Kushi L.H. Folsom A.R. 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: 1302-1317Crossref PubMed Scopus (236) Google Scholar; Kearney et al., 1996Kearney J. Giovannucci E. Rimm E.B. Ascherio A. Stampfer M.J. Colditz G.A. et al.Calcium, vitamin D, and dairy foods and the occurrence of colon cancer in men.Am J Epidemiol. 1996; 143: 907-917Crossref PubMed Scopus (177) Google Scholar), is strong. However, several large epidemiologic surveys have not demonstrated such a correlation with skin cancer (Hunter et al., 1992Hunter D.J. Colditz G.A. Stampfer M.J. Rosner B. Willett W.C. Speizer F.E. Diet and risk of basal cell carcinoma of the skin in a prospective cohort of women.Ann Epidemiol. 1992; 2: 231-239Abstract Full Text PDF PubMed Scopus (89) Google Scholar; Weinstock et al., 1992Weinstock M.A. Stampfer M.J. Lew R.A. Willett W.C. Sober A.J. Case–control study of melanoma and dietary vitamin D: implications for advocacy of sun protection and sunscreen use.J Invest Dermatol. 1992; 98: 809-811Crossref PubMed Scopus (72) Google Scholar; van Dam et al., 2000van Dam R.M. Huang Z. Giovannucci E. Rimm E.B. Hunter D.J. Colditz G.A. et al.Diet and basal cell carcinoma of the skin in a prospective cohort of men.Am J Clin Nutr. 2000; 71: 135-141PubMed Google Scholar). One potential complication is that UVB radiation has the dual effect of promoting vitamin D3 synthesis in the skin (which can be further converted to 1,25(OH)2D3) and increasing DNA damage, leading to skin cancer. Thus, although UVR may be an efficient means of providing the nutritional requirement for vitamin D, the advantage to the skin may be countered by the increased risk of mutagenesis. However, recent studies indicate that the skin has evolved a vitamin D signaling mechanism whereby the harmful effects of UVR may be mitigated. The study by Ellison et al., 2008Ellison T.I. Smith M.K. Gilliam A.C. MacDonald P.N. Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis.J Invest Dermatol. 2008; 128: 2508-2517Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar in this issue demonstrates the protective role of VDR for UVR-induced skin tumors. Earlier studies indicated that mice null for VDR were highly susceptible to epidermal tumor formation induced by either the oral administration of the carcinogen 7,12-dimethylbenzanthracene (DMBA) (Zinser et al., 2002Zinser G.M. Sundberg J.P. Welsh J. Vitamin D(3) receptor ablation sensitizes skin to chemically induced tumorigenesis.Carcinogenesis. 2002; 23: 2103-2109Crossref PubMed Scopus (161) Google Scholar) or its topical application (Indra et al., 2007Indra A.K. Castaneda E. Antal M.C. Jiang M. Messaddeq N. Meng X. et al.Malignant transformation of DMBA/TPA-induced papillomas and nevi in the skin of mice selectively lacking retinoid-X-receptor α in epidermal keratinocytes.J Invest Dermatol. 2007; 127: 1250-1260Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). In the former study, the tumors were mostly papillomas, but several BCCs were observed. No SCCs were reported. In the latter study, only benign tumors were seen in the VDR null mice, unlike RXRα null mice, which developed both BCCs and SCCs (Indra et al., 2007Indra A.K. Castaneda E. Antal M.C. Jiang M. Messaddeq N. Meng X. et al.Malignant transformation of DMBA/TPA-induced papillomas and nevi in the skin of mice selectively lacking retinoid-X-receptor α in epidermal keratinocytes.J Invest Dermatol. 2007; 127: 1250-1260Abstract Full Text Full Text PDF PubMed Scopus (63) Google Scholar). Ellison et al., 2008Ellison T.I. Smith M.K. Gilliam A.C. MacDonald P.N. Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis.J Invest Dermatol. 2008; 128: 2508-2517Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar confirmed the report by Zinser et al., 2002Zinser G.M. Sundberg J.P. Welsh J. Vitamin D(3) receptor ablation sensitizes skin to chemically induced tumorigenesis.Carcinogenesis. 2002; 23: 2103-2109Crossref PubMed Scopus (161) Google Scholar demonstrating that oral administration of DMBA induced skin tumors in all of the VDR null mice and none of the wild-type mice. Furthermore, most of the tumors that formed appeared to originate from the folliculosebaceous unit. Importantly, Ellison et al., 2008Ellison T.I. Smith M.K. Gilliam A.C. MacDonald P.N. Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis.J Invest Dermatol. 2008; 128: 2508-2517Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar did not report increased susceptibility to DMBA-induced tumor formation in mice lacking the enzyme for 1,25(OH)2D3 production (CYP27B1). The authors thus concluded that, at least for DMBA induction of tumors, VDR protection does not require its principal ligand, 1,25(OH)2D3. At this point the authors turned their attention to UVR-induced skin tumors comparing VDR null mice with wild-type controls. The mice were of C57BL/6 background, a strain relatively resistant to UVR-induced skin tumors. Even at the very high doses of UVB used in these experiments, only 4 of 23 wild-type mice developed tumors by 45 weeks after the start of UVR, 1 of which was classified as an SCC. In contrast, all 22 of the VDR null mice developed tumors, and 10 of the 27 tumors analyzed were classified as SCC, although markers to document this classification were not provided. Taken at face value, therefore, it would appear that UVR-induced tumors in VDR null mice differ in type compared with DMBA-induced tumors, with SCC predominating following UVR and BCC and folliculosebaceous tumors predominating after DMBA.Protection by VDR for UVR-induced tumors. Protection by VDR for UVR-induced tumors. Potential mechanisms were then explored. The skin of VDR null mice appeared to have greater cyclobutane pyrimidine dimer formation following UVR, suggesting a DNA repair deficiency. Previous studies with cultured keratinocytes have demonstrated that 1,25(OH)2D3 and analogs not thought to act via the nuclear configuration of the VDR were also protective against UVR-induced cyclobutane pyrimidine dimer formation (or accelerated their repair) (Dixon et al., 2005Dixon K.M. Deo S.S. Wong G. Slater M. Norman A.W. Bishop J.E. et al.Skin cancer prevention: a possible role of 1,25dihydroxyvitamin D3 and its analogs.J Steroid Biochem Mol Biol. 2005; 97: 137-143Crossref PubMed Scopus (120) Google Scholar; Gupta et al., 2007Gupta R. Dixon K.M. Deo S.S. Holliday C.J. Slater M. Halliday G.M. et al.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: 707-715Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar). Ellison et al., 2008Ellison T.I. Smith M.K. Gilliam A.C. MacDonald P.N. Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis.J Invest Dermatol. 2008; 128: 2508-2517Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar did not test whether CYP27B1 null mice were also predisposed to UVR-induced tumor formation, so the results in their article are silent as to whether this is a 1,25(OH)2D3-independent action of VDR. Apoptosis following a single exposure to UVR was reduced in VDR null mice, although no differences between wild-type and null mice were shown for p53 induction by UVR. These observations are discordant with earlier observations (De Haes et al., 2003De Haes P. Garmyn M. Degreef H. Vantieghem K. Bouillon R. Segaert S. 1,25-Dihydroxyvitamin D3 inhibits ultraviolet B-induced apoptosis, Jun kinase activation, and interleukin-6 production in primary human keratinocytes.J Cell Biochem. 2003; 89: 663-673Crossref PubMed Scopus (107) Google Scholar) that 1,25(OH)2D3 increases p53 levels and protects keratinocytes from UVR-induced apoptosis (Gupta et al., 2007Gupta R. Dixon K.M. Deo S.S. Holliday C.J. Slater M. Halliday G.M. et al.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: 707-715Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar), suggesting that VDR and 1,25(OH)2D3 might have opposite effects in these responses to UVR. This possibility could be tested by comparing the responses in CYP27B1 null mice to those in VDR null mice. The proliferative response to UVR was also slightly reduced in the VDR null epidermis, which, despite the decrease in apoptosis, seems to have resulted in a thinner epidermis in the VDR null compared with wild-type mice, although UVR induced epidermal thickening compared with the nonirradiated controls of either genotype. This result is consistent with earlier studies (De Haes et al., 2003De Haes P. Garmyn M. Degreef H. Vantieghem K. Bouillon R. Segaert S. 1,25-Dihydroxyvitamin D3 inhibits ultraviolet B-induced apoptosis, Jun kinase activation, and interleukin-6 production in primary human keratinocytes.J Cell Biochem. 2003; 89: 663-673Crossref PubMed Scopus (107) Google Scholar; Gupta et al., 2007Gupta R. Dixon K.M. Deo S.S. Holliday C.J. Slater M. Halliday G.M. et al.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: 707-715Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar) demonstrating that 1,25(OH)2D3 enhances cell survival in keratinocytes after UVR, but it again raises the question of whether these are 1,25(OH)2D3-dependent or -independent actions of VDR. The finding of the thinner epidermis in the VDR null mouse relative to controls is surprising, however, considering the higher proliferation rates in the epidermis and underlying folliculosebaceous unit of the VDR null mouse compared with controls under basal conditions (Xie et al., 2002Xie Z. Komuves L. Yu Q.C. Elalieh H. Ng D.C. Leary C. et al.Lack of the vitamin D receptor is associated with reduced epidermal differentiation and hair follicle growth.J Invest Dermatol. 2002; 118: 11-16Crossref PubMed Scopus (147) Google Scholar; Bikle et al., 2006Bikle D.D. Elalieh H. Chang S. Xie Z. Sundberg J.P. Development and progression of alopecia in the vitamin D receptor null mouse.J Cell Physiol. 2006; 207: 340-353Crossref PubMed Scopus (65) Google Scholar). What, then, might be the underlying mechanisms? The DMBA studies producing tumors primarily of folliculosebaceous origin suggest that Hh signaling might be altered in VDR null skin. Appreciation of the pivotal role of the Hh signaling pathway in epidermal carcinogenesis began with the identification of the Ptch1 gene as the site of mutations underlying the rare autosomal dominant heritable basal-cell nevus syndrome (Gorlin's syndrome), one cardinal feature of which is a high susceptibility to the development of BCCs (Hahn et al., 1996Hahn H. Wicking C. Zaphiropoulous P.G. Gailani M.R. Shanley S. Chidambaram A. et al.Mutations of the human homolog of Drosophila patched in the nevoid basal cell carcinoma syndrome.Cell. 1996; 85: 841-851Abstract Full Text Full Text PDF PubMed Scopus (1611) Google Scholar; Aszterbaum et al., 1998Aszterbaum M. Rothman A. Johnson R.L. Fisher M. Xie J. Bonifas J.M. et al.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: 885-888Crossref PubMed Scopus (239) Google Scholar). The BCCs in these subjects frequently lose function of the inherited wild-type Ptch1 allele, leaving the tumor cells functionally null of Ptch1. It has subsequently become clear that essentially all BCCs, whether arising in patients with basal cell nevus syndrome or sporadically, have mutations in Ptch1 or other alterations in Hh signaling (Aszterbaum et al., 1999Aszterbaum M. Epstein J. Oro A. Douglas V. LeBoit P.E. Scott M.P. et al.Ultraviolet and ionizing radiation enhance the growth of BCCs and trichoblastomas in patched heterozygous knockout mice.Nat Med. 1999; 5: 1285-1291Crossref PubMed Scopus (326) Google Scholar). This appreciation has resulted in the development of the Ptch1+/- (Gorlin) mouse as the first practical model of murine BCC (Regl et al., 2004aRegl G. Kasper M. Schnidar H. Eichberger T. Neill G.W. Ikram M.S. et al.The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells.Oncogene. 2004; 23: 1263-1274Crossref PubMed Scopus (75) Google Scholar). Treatment of these mice (unlike treatment of Ptch1 wild-type mice) with UVR or ionizing radiation produces BCC as well as SCC (Regl et al., 2004aRegl G. Kasper M. Schnidar H. Eichberger T. Neill G.W. Ikram M.S. et al.The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells.Oncogene. 2004; 23: 1263-1274Crossref PubMed Scopus (75) Google Scholar). Ptch1 is the membrane receptor for sonic hedgehog (Shh). In the absence of Shh, Ptch1 inhibits the function of another membrane protein, smoothened (Smoh). Shh reverses this inhibition, freeing Smoh to enable the activation of a family of transcription factors, Gli1 and Gli2. Gli1 and -2 overexpression in keratinocytes can increase the expression of each other as well as Ptch1, the anti-apoptotic factor bcl2, cyclins D1 and D2, E2F1, and cdc45 (all of which promote proliferation) while suppressing genes associated with keratinocyte differentiation such as K1, K10, involucrin, loricrin and VDR (Grachtchouk et al., 2000Grachtchouk M. Mo R. Yu S. Zhang X. Sasaki H. Hui C.C. et al.Basal cell carcinomas in mice overexpressing Gli2 in skin.Nat Genet. 2000; 24: 216-217Crossref PubMed Scopus (313) Google Scholar; Nilsson et al., 2000Nilsson M. Unden A.B. Krause D. Malmqwist U. Raza K. Zaphiropoulos P.G. et al.Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1.Proc Natl Acad Sci USA. 2000; 97: 3438-3443Crossref PubMed Scopus (339) Google Scholar; Regl et al., 2002Regl G. Neill G.W. Eichberger T. Kasper M. Ikram M.S. Koller J. et al.Human GLI2 and GLI1 are part of a positive feedback mechanism in basal cell carcinoma.Oncogene. 2002; 21: 5529-5539Crossref PubMed Scopus (157) Google Scholar, Regl et al., 2004aRegl G. Kasper M. Schnidar H. Eichberger T. Neill G.W. Ikram M.S. et al.The zinc-finger transcription factor GLI2 antagonizes contact inhibition and differentiation of human epidermal cells.Oncogene. 2004; 23: 1263-1274Crossref PubMed Scopus (75) Google Scholar, Regl et al., 2004bRegl G. Kasper M. Schnidar H. Eichberger T. Neill G.W. Philpott M.P. et al.Activation of the BCL2 promoter in response to Hedgehog/GLI signal transduction is predominantly mediated by GLI2.Cancer Res. 2004; 64: 7724-7731Crossref PubMed Scopus (197) Google Scholar). Mice overexpressing Gli1, Gli2, or Shh in their basal keratinocytes (Oro et al., 1997Oro A.E. Higgins K.M. Hu Z. Bonifas J.M. Epstein Jr, E.H. Scott M.P. Basal cell carcinomas in mice overexpressing sonic hedgehog.Science. 1997; 276: 817-821Crossref PubMed Scopus (580) Google Scholar; Grachtchouk et al., 2000Grachtchouk M. Mo R. Yu S. Zhang X. Sasaki H. Hui C.C. et al.Basal cell carcinomas in mice overexpressing Gli2 in skin.Nat Genet. 2000; 24: 216-217Crossref PubMed Scopus (313) Google Scholar; Nilsson et al., 2000Nilsson M. Unden A.B. Krause D. Malmqwist U. Raza K. Zaphiropoulos P.G. et al.Induction of basal cell carcinomas and trichoepitheliomas in mice overexpressing GLI-1.Proc Natl Acad Sci USA. 2000; 97: 3438-3443Crossref PubMed Scopus (339) Google Scholar) or grafted with human keratinocytes overexpressing Shh (Fan et al., 1997Fan H. Oro A.E. Scott M.P. Khavari P.A. Induction of basal cell carcinoma features in transgenic human skin expressing Sonic Hedgehog.Nat Med. 1997; 3: 788-792Crossref PubMed Scopus (230) Google Scholar) develop BCC-like lesions. Furthermore, BCCs demonstrate overexpression of Ptch1, Smoh, Gli1, and Gli2 (Tojo et al., 1999Tojo M. Mori T. Kiyosawa H. Honma Y. Tanno Y. Kanazawa K.Y. et al.Expression of sonic hedgehog signal transducers, patched and smoothened, in human basal cell carcinoma.Pathol Int. 1999; 49: 687-694Crossref PubMed Scopus (39) Google Scholar; Bonifas et al., 2001Bonifas J.M. Pennypacker S. Chuang P.T. McMahon A.P. Williams M. Rosenthal A. et al.Activation of expression of hedgehog target genes in basal cell carcinomas.J Invest Dermatol. 2001; 116: 739-742Crossref PubMed Scopus (120) Google Scholar). A number of the Hh pathway components, including both Gli1 and -2, have consensus vitamin D response elements in their promoters (Wang et al., 2005Wang T.T. Tavera-Mendoza L.E. Laperriere D. Libby E. MacLeod N.B. Nagai Y. et al.Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes.Mol Endocrinol. 2005; 19: 2685-2695Crossref PubMed Scopus (441) Google Scholar; Palmer et al., 2008Palmer H.G. Anjos-Afonso F. Carmeliet G. Takeda H. Watt F.M. The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis.PLoS ONE. 2008; 3: e1483Crossref PubMed Scopus (115) Google Scholar). We (A. Teichert, J. Welsh, and D. Bikle, unpublished data) reported that the epidermis and epidermal portion (utricles) of the hair follicles of VDR null animals overexpress elements of the Hh signaling pathway, suggesting that one of the causes of the increased susceptibility of the epidermis to malignant transformation is a loss of VDR regulation of Hh signaling. The wnt signaling pathway may also be involved. In a recent paper, Palmer et al., 2008Palmer H.G. Anjos-Afonso F. Carmeliet G. Takeda H. Watt F.M. The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis.PLoS ONE. 2008; 3: e1483Crossref PubMed Scopus (115) Google Scholar reported the interaction of VDR and wnt signaling in the regulation of hair follicle differentiation and tumor formation. The authors identified various combinations of putative vitamin D response elements and lymphoid-enhancing factor/T-cell factor response elements in a number of genes involved with epidermal and hair follicle differentiation, including components of the Hh signaling pathway such as Shh, Ptch2, and Gli1 and -2, as well as in LEF itself, the transcriptional partner for β-catenin critical for wnt signaling. At least in colon cancer cells, 1,25(OH)2D3 inhibits the tumor-promoting properties of β-catenin by inducing E-cadherin, to which β-catenin binds (Palmer et al., 2001Palmer H.G. Gonzalez-Sancho J.M. Espada J. Berciano M.T. Puig I. Baulida J. et al.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: 369-387Crossref PubMed Scopus (644) Google Scholar), and promoting the binding of VDR to β-catenin (Shah et al., 2006Shah S. Islam M.N. Dakshanamurthy S. Rizvi I. Rao M. Herrell R. et al.The molecular basis of vitamin D receptor and beta-catenin crossregulation.Mol Cell. 2006; 21: 799-809Abstract Full Text Full Text PDF PubMed Scopus (212) Google Scholar), thus limiting its nuclear localization and transcriptional activity. Palmer et al., 2008Palmer H.G. Anjos-Afonso F. Carmeliet G. Takeda H. Watt F.M. The vitamin D receptor is a Wnt effector that controls hair follicle differentiation and specifies tumor type in adult epidermis.PLoS ONE. 2008; 3: e1483Crossref PubMed Scopus (115) Google Scholar demonstrated in skin that lack of VDR predisposes the mouse to develop BCC when active β-catenin was overexpressed, although the link to increased Hh signaling was not explored. In addition to suppression of Hh and wnt signaling, a third mechanism may also be at work, the DNA damage response (DDR). Many endogenous and exogenous factors, including oncogenes, tumor suppressors, radiation, chemical carcinogens, and viral infections, impact a common, but complex, set of pathways that regulate cellular survival, apoptosis, and genomic stability: DDR and the cell cycle checkpoints (Bartkova et al., 2005Bartkova J. Horejsi Z. Koed K. Kramer A. Tort F. Zieger K. et al.DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis.Nature. 2005; 434: 864-870Crossref PubMed Scopus (2119) Google Scholar, Bartkova et al., 2006Bartkova J. Rezaei N. Liontos M. Karakaidos P. Kletsas D. Issaeva N. et al.Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints.Nature. 2006; 444: 633-637Crossref PubMed Scopus (1401) Google Scholar). DDR involves a cascade of damage recognition, repair, and signal transduction that coordinates the response of the cell cycle to DNA damage. DDR activates checkpoints that delay the cell cycle, providing time for repair, and directs damaged cells into senescent or apoptotic pathways. DDR demonstrates wide variation in components, activation signals, and downstream consequences according to the cell types, species, and damaging agents. DDR is tightly controlled and highly accurate in normal primary cells such that the spontaneous mutation rate is very low and changes in copy number are negligible (Tlsty et al., 1989Tlsty T.D. Margolin B.H. Lum K. Differences in the rates of gene amplification in nontumorigenic and tumorigenic cell lines as measured by Luria–Delbruck fluctuation analysis.Proc Natl Acad Sci USA. 1989; 86: 9441-9445Crossref PubMed Scopus (204) Google Scholar; Tlsty, 1990Tlsty T.D. Normal diploid human and rodent cells lack a detectable frequency of gene amplification.Proc Natl Acad Sci USA. 1990; 87: 3132-3136Crossref PubMed Scopus (162) Google Scholar; Bielas et al., 2006Bielas J.H. Loeb K.R. Rubin B.P. True L.D. Loeb L.A. Human cancers express a mutator phenotype.Proc Natl Acad Sci USA. 2006; 103: 18238-18242Crossref PubMed Scopus (276) Google Scholar). During malignant transformation, a DNA repair "barrier" is abrogated (Bartkova et al., 2005Bartkova J. Horejsi Z. Koed K. Kramer A. Tort F. Zieger K. et al.DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis.Nature. 2005; 434: 864-870Crossref PubMed Scopus (2119) Google Scholar, Bartkova et al., 2006Bartkova J. Rezaei N. Liontos M. Karakaidos P. Kletsas D. Issaeva N. et al.Oncogene-induced senescence is part of the tumorigenesis barrier imposed by DNA damage checkpoints.Nature. 2006; 444: 633-637Crossref PubMed Scopus (1401) Google Scholar), DDR becomes less controlled, and mutation rates and copy number changes increase by orders of magnitude (Tlsty et al., 1989Tlsty T.D. Margolin B.H. Lum K. Differences in the rates of gene amplification in nontumorigenic and tumorigenic cell lines as measured by Luria–Delbruck fluctuation analysis.Proc Natl Acad Sci USA. 1989; 86: 9441-9445Crossref PubMed Scopus (204) Google Scholar; Bielas et al., 2006Bielas J.H. Loeb K.R. Rubin B.P. True L.D. Loeb L.A. Human cancers express a mutator phenotype.Proc Natl Acad Sci USA. 2006; 103: 18238-18242Crossref PubMed Scopus (276) Google Scholar). DDR from UV-induced photoproducts has distinct G1 and S phase responses. Nucleotide excision repair (NER) in G1, for example, excises UV photoproducts before onset of DNA replication and thereby eliminates mutagenic lesions completely (Maher et al., 1979Maher V.M. Dorney D.J. Mendrala A.L. Konze-Thomas B. McCormick J.J. DNA excision–repair processes in human cells can eliminate the cytotoxic and mutagenic consequences of ultraviolet irradiation.Mutat Res. 1979; 62: 311-323Crossref PubMed Scopus (190) Google Scholar). The main substrates for NER are the UV photoproducts between adjacent pyrimidines: cyclobutane pyrimidine dimers and pyrimidine (6-4) pyrimidone photoproducts (Cleaver et al., 2005), lesions produced by UVB. Mutations in NER genes are associated with several human cancer and neurodegenerative diseases, especially xeroderma pigmentosum (XP) and Cockayne's syndrome (Hoeijmakers, 2001Hoeijmakers J.H. Genome maintenance mechanisms for preventing cancer.Nature. 2001; 411: 366-374Crossref PubMed Scopus (2989) Google Scholar; Wood et al., 2001Wood R.D. Mitchell M. Sgouros J. Lindahl T. Human DNA repair genes.Science. 2001; 291: 1284-1289Crossref PubMed Scopus (1067) Google Scholar). Damage in transcribed genes is recognized through the arrest of RNA Pol II, which is relieved through the action of two proteins, CSA and CSB. Damage in the nontranscribed or global regions of the genome is recognized by the binding of two heterodimeric XP proteins, XPE (DDB1/DDB2) and XPC/HR23B, which may act in concert to bind to damaged DNA (Hoeijmakers, 2001Hoeijmakers J.H. Genome maintenance mechanisms for preventing cancer.Nature. 2001; 411: 366-374Crossref PubMed Scopus (2989) Google Scholar). These converge on a common pathway through which the damage is verified (XPA/RPA), the DNA is unwound by the XPB and XPD helicase components of the transcription factor TFIIH, cleaved by structure-specific nucleases (XPG, XPF/ERCC1), and the damage is excised and replaced. The global branch of the NER (GGR: XP-A through G) pathway is strongly influenced by transactivation of the XPC and XPE genes by p53 through DNA damage-dependent increases in p53 expression. GGR defects increase carcinogenesis (Berg et al., 2000Berg R.J. Rebel H. van der Horst G.T. van Kranen H.J. Mullenders L.H. van Vloten W.A. et al.Impact of global genome repair versus transcription-coupled repair on ultraviolet carcinogenesis in hairless mice.Cancer Res. 2000; 60: 2858-2863PubMed Google Scholar). As noted above, recent studies have shown that vitamin D may have a strong regulatory effect on the capacity of cells and skin to carry out DDR. Treatment of the skin with 1,25(OH)2D3 rapidly increased photoproduct excision in human and mouse cells and tissues (Dixon et al., 2005Dixon K.M. Deo S.S. Wong G. Slater M. Norman A.W. Bishop J.E. et al.Skin cancer prevention: a possible role of 1,25dihydroxyvitamin D3 and its analogs.J Steroid Biochem Mol Biol. 2005; 97: 137-143Crossref PubMed Scopus (120) Google Scholar; Gupta et al., 2007Gupta R. Dixon K.M. Deo S.S. Holliday C.J. Slater M. Halliday G.M. et al.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: 707-715Abstract Full Text Full Text PDF PubMed Scopus (121) Google Scholar), but the mechanism of interaction with NER remains unclear. However, when Moll et al., 2007Moll P.R. Sander V. Frischauf A.M. Richter K. Expression profiling of vitamin D treated primary human keratinocytes.J Cell Biochem. 2007; 100: 574-592Crossref PubMed Scopus (32) Google Scholar performed microarray studies of keratinocytes treated with 1,25(OH)2D3 for 24 hours, they observed an upregulation of two genes important for DDR: XPC and DDB2/XPE. Accordingly, 1,25(OH)2D3 and VDR may be protective against UVR-induced epidermal tumor formation by stimulating DDR as well as by suppressing Hh and wnt signaling. Ellison et al., 2008Ellison T.I. Smith M.K. Gilliam A.C. MacDonald P.N. Inactivation of the vitamin D receptor enhances susceptibility of murine skin to UV-induced tumorigenesis.J Invest Dermatol. 2008; 128: 2508-2517Abstract Full Text Full Text PDF PubMed Scopus (120) Google Scholar make the important point that VDR serves as a tumor suppressor not only for chemically induced epidermal carcinogenesis but also for the more physiologically relevant UVR-induced epidermal carcinogenesis. Although these authors have convincingly demonstrated that the former is a 1,25(OH)2D3-independent action of VDR, this conclusion cannot yet be extended to UVR-induced carcinogenesis. Earlier studies indicated several mechanisms by which VDR, with or without its ligand 1,25(OH)2D3, might be protective. These mechanisms include altered Hh and wnt signaling and increased DDR. Future investigations are required to determine which, if any, of these mechanisms are involved and the degree to which VDR acts through these mechanisms in a 1,25(OH)2D3-dependent or -independent manner. However, this publication establishes an important fact: the skin has evolved a way of protecting itself from the deleterious actions of UVR using a key component of the pathway promoted by UVR, namely, the VDR. The author states no conflict of interest. The author appreciates helpful discussions with James Cleaver, Dennis Oh, Yuko Oda, and Arnaud Teichert regarding the content of the paper. The writing of the manuscript was supported in part by grants to the author from the National Institutes of Health (PO1 AR39448, RO1 AR0550023), the Veterans Affairs Merit Review system, and the American Institute for Cancer Research.

Referência(s)