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

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Vitamin D Receptor, UVR, and Skin Cancer: a Potential Protective Mechanism CORE Metadata, citation and similar papers at core.ac.uk Provided by Elsevier - Publisher Connector COMMENTARY See related article on pg 2508 of cancers, including those of the colon, breast, and prostate (Bostick et al., 1993; Garland et al., 1985, 1990; Vitamin D Receptor, UVR, Hanchette and Schwartz, 1992; Kearney et al., 1996), is strong. However, sev- and Skin Cancer: A Potential eral large epidemiologic surveys have not demonstrated such a correlation Protective Mechanism with skin cancer (Hunter et al., 1992; Daniel D. Bikle1 van Dam et al., 2000; Weinstock et al., 1992). One potential complica- More than 1 million skin cancers occur annually in the United States—of tion is that UVB radiation has the dual which 80% are basal-cell carcinoma (BCC), 16% are squamous-cell carcinoma effect of promoting vitamin D3 synthesis (SCC), and 4% are melanomas—making skin cancer by far the most common in the skin (which can be further con- cancer (Greenlee et al., 2001). UVR is the major etiologic agent. UV wave- verted to 1,25(OH)2D3) and increasing lengths shorter than 280 nm (UVC) are absorbed by the ozone layer and do DNA damage, leading to skin cancer. not reach the earth. UV wavelengths longer than 320 nm (UVA) have limited Thus, although UVR may be an effi- ability to induce the characteristic mutations in DNA seen in epidermal can- cient means of providing the nutritional cers. Thus, UVB, with a spectrum between 280 and 320 nm, is the major cause requirement for vitamin D, the advan- of these cancers (Freeman et al., 1989), but this is the same spectrum required tage to the skin may be countered by the for vitamin D production in the skin. Is there a link? increased risk of mutagenesis. However, Journal of Investigative Dermatology (2008), 128, 2357–2361. doi:10.1038/jid.2008.249 recent studies indicate that the skin has evolved a vitamin D signaling mecha- nism whereby the harmful effects of UVR may be mitigated. The principal genotoxic lesions SCCs (Danaee et al., 2006), and poly- The study by Ellison et al. (2008) induced by UVR are cyclobutane morphisms of the Ptch1 gene have in this issue demonstrates the protec- pyrimidine dimers and pyrimidine (6-4) altered the resistance to SCC formation tive role of VDR for UVR-induced skin pyrimidone photoproducts, which, if in mice expressing an activated ras tumors. Earlier studies indicated that not repaired, result in C-to-T or CC-to- oncogene (Wakabayashi et al., 2007). mice null for VDR were highly sus- TT mutations, the UVB “signature” Thus, alterations in the Hh signaling ceptible to epidermal tumor formation lesion (Hussein, 2005). Mutations in pathway contribute to the formation of induced by either the oral administra- p53 are common (50–90%) in both both SCC and BCC. tion of the carcinogen 7,12-dimethyl- BCC and SCC (Brash et al., 1991; 1,25-Dihydroxyvitamin D3 (1,25 benzanthracene (DMBA) (Zinser et al., Daya-Grosjean and Sarasin, 2005; (OH)2D3) has been evaluated for its 2002) or its topical application (Indra Ziegler et al., 1993, 1994), as well potential anticancer activity for approx- et al., 2007). In the former study, the as in actinic keratoses, the precur- imately 25 years (Eisman et al., 1979). tumors were mostly papillomas, but sor lesions to SCC (Bito et al., 1995). The list of malignant cells that express several BCCs were observed. No SCCs Precursor lesions for BCC have not the receptor for 1,25(OH)2D3—vitamin were reported. In the latter study, only been identified, but BCCs are thought D receptor (VDR)—is now quite benign tumors were seen in the VDR to arise from interfollicular basal cells, extensive and for the purposes of this null mice, unlike RXRα null mice, hair follicles, and sebaceous glands. Commentary includes BCCs and SCCs which developed both BCCs and SCCs Mutations in ras are much more com- (Kamradt et al., 2003; Ratnam et al., (Indra et al., 2007). Ellison et al. (2008) mon in SCC than in BCC (Reifenberger 1996), as well as melanomas (Colston confirmed the report by Zinser et al. et al., 2005), whereas mutations in the et al., 1981). The accepted basis for (2002) demonstrating that oral admin- hedgehog (Hh) signaling pathway— the promise of 1,25(OH)2D3 in the pre- istration of DMBA induced skin tumors in particular, in patched 1 (Ptch1)— vention and treatment of malignancy in all of the VDR null mice and none of characterize BCC (Aszterbaum et includes its antiproliferative, prodif- the wild-type mice. Furthermore, most al., 1998, 1999; Hahn et al., 1996; ferentiating effects on most cell types. of the tumors that formed appeared to Johnson et al., 1996). However, loss Epidemiologic evidence supporting originate from the folliculosebaceous of heterozygosity in the region includ- the importance of adequate vitamin unit. Importantly, Ellison et al. (2008) ing the Ptch1 gene has been reported D nutrition (including sunlight expo- did not report increased susceptibil- in a high percentage of both BCCs and sure) for the prevention of a number ity to DMBA-induced tumor forma- tion in mice lacking the enzyme for 1,25(OH) D production (CYP27B1). 1Department of Medicine, University of California San Francisco/VA Medical Center, San Francisco, 2 3 California, USA The authors thus concluded that, at Correspondence: Dr Daniel D. Bikle, Department of Medicine, University of California San Francisco/VA least for DMBA induction of tumors, Medical Center, 4150 Clement Street, San Francisco, California 94121, USA. VDR protection does not require its E-mail: [email protected] principal ligand, 1,25(OH)2D3. www.jidonline.org 2357 COMMENTARY At this point the authors turned with earlier observations (De Haes et have mutations in Ptch1 or other alter- their attention to UVR-induced skin al., 2003) that 1,25(OH)2D3 increases ations in Hh signaling (Aszterbaum tumors comparing VDR null mice with p53 levels and protects keratinocytes et al., 1999). This appreciation has wild-type controls. The mice were of from UVR-induced apoptosis (Gupta resulted in the development of the C57BL/6 background, a strain rela- et al., 2007), suggesting that VDR Ptch1+/– (Gorlin) mouse as the first tively resistant to UVR-induced skin and 1,25(OH)2D3 might have oppo- practical model of murine BCC (Regl site effects in these responses to UVR. et al., 2004a). Treatment of these mice This possibility could be tested by (unlike treatment of Ptch1 wild-type comparing the responses in CYP27B1 mice) with UVR or ionizing radiation Protection by VDR for null mice to those in VDR null mice. produces BCC as well as SCC (Regl UVR-induced tumors. The proliferative response to UVR et al., 2004a). Ptch1 is the membrane was also slightly reduced in the VDR receptor for sonic hedgehog (Shh). | null epidermis, which, despite the In the absence of Shh, Ptch1 inhib- decrease in apoptosis, seems to have its the function of another membrane resulted in a thinner epidermis in the protein, smoothened (Smoh). Shh VDR null compared with wild-type reverses this inhibition, freeing Smoh tumors. Even at the very high doses of mice, although UVR induced epider- to enable the activation of a family of UVB used in these experiments, only mal thickening compared with the transcription factors, Gli1 and Gli2. 4 of 23 wild-type mice developed nonirradiated controls of either gen- Gli1 and -2 overexpression in keratin- tumors by 45 weeks after the start of otype. This result is consistent with ocytes can increase the expression of UVR, 1 of which was classified as an earlier studies (De Haes et al., 2003; each other as well as Ptch1, the anti- SCC. In contrast, all 22 of the VDR null Gupta et al., 2007) demonstrating that apoptotic factor bcl2, cyclins D1 and mice developed tumors, and 10 of the 1,25(OH)2D3 enhances cell survival in D2, E2F1, and cdc45 (all of which 27 tumors analyzed were classified as keratinocytes after UVR, but it again promote proliferation) while suppress- SCC, although markers to document raises the question of whether these ing genes associated with keratinocyte this classification were not provided. are 1,25(OH)2D3-dependent or -inde- differentiation such as K1, K10, invo- Taken at face value, therefore, it would pendent actions of VDR. The finding of lucrin, loricrin and VDR (Grachtchouk appear that UVR-induced tumors in the thinner epidermis in the VDR null et al., 2000; Nilsson et al., 2000; Regl VDR null mice differ in type compared mouse relative to controls is surpris- et al., 2002, 2004a,b). Mice overex- with DMBA-induced tumors, with SCC ing, however, considering the higher pressing Gli1, Gli2, or Shh in their predominating following UVR and proliferation rates in the epidermis basal keratinocytes (Grachtchouk et BCC and folliculosebaceous tumors and underlying folliculosebaceous al., 2000; Nilsson et al., 2000; Oro et predominating after DMBA. unit of the VDR null mouse compared al., 1997) or grafted with human kera- Potential mechanisms were then with controls under basal conditions tinocytes overexpressing Shh (Fan et explored. The skin of VDR null mice (Bikle et al., 2006; Xie et al., 2002). al., 1997) develop BCC-like lesions. appeared to have greater cyclobutane What, then, might be the underlying Furthermore, BCCs demonstrate over- pyrimidine dimer formation following mechanisms? The DMBA studies pro- expression of Ptch1, Smoh, Gli1, and UVR, suggesting a DNA repair defi- ducing tumors primarily of folliculo- Gli2 (Bonifas et al., 2001; Tojo et al., ciency. Previous studies with cultured sebaceous origin suggest that Hh 1999). A number of the Hh pathway keratinocytes have demonstrated that signaling might be altered in VDR null components, including both Gli1 and 1,25(OH)2D3 and analogs not thought skin.
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