UV Radiation, Vitamin D and Epidermal Carcinogenesis
Daniel D Bikle
Abstract
The skin is the major source of vitamin D in the body, being the site where the precursor 7-dehydrocholesterol is converted to vitamin D under the influence of UVB radiation (UVR). Unfortunately, UVR is also the major cause of nonmelanoma skin cancer (NMSC). Substantial evidence from epidemiologic and animal studies demonstrates an important protective effect of vitamin D for a number of cancers, but the evidence is weaker for NMSC. However, recent studies indicate that animals lacking the vitamin D receptor are predisposed to developing NMSC following UVR or chemical carcinogens, suggesting that vitamin D and its active metabolite 1,25-dihydroxyvitamin D3 may also be protective of NMSC. The mechanisms underlying this protective mechanism include regulation of the hedgehog and â-catenin pathways and stimulation of the DNA damage response. This article will examine the evidence supporting this potential protective action of vitamin D with respect to NMSC development.
The skin is the major source of vitamin D in the body, being the site where the precursor 7-dehydrocholesterol is converted to vitamin D under the influence of UVB radiation (UVR). Unfortunately, UVR is also the major cause of nonmelanoma skin cancer (NMSC). Substantial evidence from epidemiologic and animal studies demonstrates an important protective effect of vitamin D for a number of cancers, but the evidence is weaker for NMSC. However, recent studies indicate that animals lacking the vitamin D receptor are predisposed to developing NMSC following UVR or chemical carcinogens, suggesting that vitamin D and its active metabolite 1,25-dihydroxyvitamin D3 may also be protective of NMSC. The mechanisms underlying this protective mechanism include regulation of the hedgehog and â-catenin pathways and stimulation of the DNA damage response. This article will examine the evidence supporting this potential protective action of vitamin D with respect to NMSC development.
Introduction
Over 1 million skin cancers occur annually in the USA, 80% of which are basal cell carcinomas (BCCs), 16% are squamous cell carcinomas (SCCs) and 4% are melanomas, making skin cancer by far the most common cancer afflicting humankind. Surgery is generally curative, however, it is also disfiguring and costly. UV radiation 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 observed in epidermal cancers. Thus, UVB with a spectrum between 280 and 320 nm is the major cause of these cancers. The principle genotoxic lesions induced by UVR are cyclobutane pyrimidine dimers (CPDs) and pyrimidine(64) pyrimidone photoproducts, which if not repaired result in C to T or CC to TT mutations, the UVB 'signature' lesion. Mutations in p53 are common in both BCC and SCC (occurring in 5090% of cases), as well as in actinic keratoses, the precursor lesions to SCC. Surprisingly, patients with Li-Fraumeni Syndrome, involving mutations in p53, are not predisposed to SCC and BCC unlike other malignancies, suggesting that other gene family members, such as p63 and p73 may play important roles in epidermal carcinogenesis. 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 BCC, whereas mutations in the hedgehog (Hh) signaling pathway, in particular in patched 1 (Ptch1), characterize BCC, but can also be found in SCC in patients also susceptible to BCC. While UVB radiation (UVR) is the major etiologic agent for these cancers, it is also the principal means by which the body obtains vitamin D. Furthermore, the skin is capable of converting the vitamin D produced to its active metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), via the enzyme CYP27B1, and this conversion is potentiated by UVR at least in part via cytokines, such as TNF-á, which are increased in the epidermis by UVR.
Sun avoidance may reduce one's risk of developing skin cancer, but this practice can result in suboptimal levels of vitamin D in the body. Most tissues express the vitamin D receptor (VDR) and several, including the epidermis, are capable of producing their own 1,25(OH)2D3. Vitamin D deficiency is associated with a number of diseases including, but not limited to, osteomalacia and rickets. Increased cancer risk ranks among these diseases, with the strongest association between vitamin D deficiency and colon cancer. This, however, has not been shown for nonmelanoma skin cancers (NMSCs). Perhaps because UVR increases the risk for NMSC, the potential for vitamin D and 1,25(OH)2D3 production in the epidermis to serve as protection against UVR-induced epidermal carcinogenesis has received little attention. However, recent studies have caused us to re-evaluate the role of vitamin D in epidermal carcinogenesis, and we propose that vitamin D production in the skin may serve as a protective mechanism for the otherwise carcinogenic actions of UVR.
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Over 1 million skin cancers occur annually in the USA, 80% of which are basal cell carcinomas (BCCs), 16% are squamous cell carcinomas (SCCs) and 4% are melanomas, making skin cancer by far the most common cancer afflicting humankind. Surgery is generally curative, however, it is also disfiguring and costly. UV radiation 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 observed in epidermal cancers. Thus, UVB with a spectrum between 280 and 320 nm is the major cause of these cancers. The principle genotoxic lesions induced by UVR are cyclobutane pyrimidine dimers (CPDs) and pyrimidine(64) pyrimidone photoproducts, which if not repaired result in C to T or CC to TT mutations, the UVB 'signature' lesion. Mutations in p53 are common in both BCC and SCC (occurring in 5090% of cases), as well as in actinic keratoses, the precursor lesions to SCC. Surprisingly, patients with Li-Fraumeni Syndrome, involving mutations in p53, are not predisposed to SCC and BCC unlike other malignancies, suggesting that other gene family members, such as p63 and p73 may play important roles in epidermal carcinogenesis. 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 BCC, whereas mutations in the hedgehog (Hh) signaling pathway, in particular in patched 1 (Ptch1), characterize BCC, but can also be found in SCC in patients also susceptible to BCC. While UVB radiation (UVR) is the major etiologic agent for these cancers, it is also the principal means by which the body obtains vitamin D. Furthermore, the skin is capable of converting the vitamin D produced to its active metabolite 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), via the enzyme CYP27B1, and this conversion is potentiated by UVR at least in part via cytokines, such as TNF-á, which are increased in the epidermis by UVR.
Sun avoidance may reduce one's risk of developing skin cancer, but this practice can result in suboptimal levels of vitamin D in the body. Most tissues express the vitamin D receptor (VDR) and several, including the epidermis, are capable of producing their own 1,25(OH)2D3. Vitamin D deficiency is associated with a number of diseases including, but not limited to, osteomalacia and rickets. Increased cancer risk ranks among these diseases, with the strongest association between vitamin D deficiency and colon cancer. This, however, has not been shown for nonmelanoma skin cancers (NMSCs). Perhaps because UVR increases the risk for NMSC, the potential for vitamin D and 1,25(OH)2D3 production in the epidermis to serve as protection against UVR-induced epidermal carcinogenesis has received little attention. However, recent studies have caused us to re-evaluate the role of vitamin D in epidermal carcinogenesis, and we propose that vitamin D production in the skin may serve as a protective mechanism for the otherwise carcinogenic actions of UVR.
DOWNLOAD COMPLETE PDF HERE
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