Vitamin D in cutaneous carcinogenesis: Part II

Department of Dermatology, Stanford University, Stanford, California. Electronic address: .
Journal of the American Academy of Dermatology (Impact Factor: 4.45). 11/2012; 67(5):817.e1-817.e11. DOI: 10.1016/j.jaad.2012.07.022
Source: PubMed


The role of vitamin D in health maintenance and disease prevention in fields ranging from bone metabolism to cancer is currently under intensive investigation. A number of epidemiologic studies have suggested that vitamin D may have a protective effect on cancer risk and cancer-associated mortality. With regard to skin cancer, epidemiologic and laboratory studies suggest that vitamin D and its metabolites may have a similar risk reducing effect. Potential mechanisms of action include inhibition of the hedgehog signaling pathway and upregulation of nucleotide excision repair enzymes. The key factor complicating the association between vitamin D and skin cancer is ultraviolet B radiation. The same spectrum of ultraviolet B radiation that catalyzes the production of vitamin D in the skin also causes DNA damage that can lead to epidermal malignancies. Part II of this continuing medical education article will summarize the literature on vitamin D and skin cancer to identify evidence-based optimal serum levels of vitamin D and to recommend ways of achieving those levels while minimizing the risk of skin cancer.

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    • "Like most other skin cells, keratinocytes express VDR (Lehmann et al., 2004; Holick, 2007); in these cells, 1,25-dihydroxyvitamin D, blocks proliferation and promotes differentiation in vitro (Lehmann et al., 2004; Holick, 2007; Haussler et al., 2012). Interestingly, it has been reported that the combination of 1,25-dihydroxyvitamin D and the retinoic acid metabolite isotretinoin is efficient in the therapy of precancerous skin lesions and of non-melanoma skin cancer (cutaneous squamous and basal cell carcinomas) (Tang et al., 2012a,b; Mason and Reichrath, 2013). Moreover, it has been demonstrated that VDR ablation promotes chemically induced skin carcinogenesis (Tang et al., 2012a,b; Mason and Reichrath, 2013). "
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    ABSTRACT: P53 and its family members have been implicated in the direct regulation of the vitamin D receptor (VDR). Vitamin D- and p53-signaling pathways have a significant impact on spontaneous or carcinogen-induced malignant transformation of cells, with VDR and p53 representing important tumour suppressors. VDR and the p53/p63/p73 proteins all function typically as receptors or sensors that turn into transcriptional regulators upon stimulus, with the main difference being that the nuclear VDR is activated as a transcription factor after binding its naturally occurring ligand 1,25-dihydroxyvitamin D with high affinity while the p53 family of transcription factors, mostly in the nucleoplasm, responds to a large number of alterations in cell homeostasis commonly referred to as stress. An increasing body of evidence now convincingly demonstrates a cross-talk between vitamin D- and p53-signaling that occurs at different levels, has genome-wide implications and that should be of high importance for many malignancies, including non-melanoma skin cancer. One interaction involves the ability of p53 to increase skin pigmentation via POMC derivatives including alpha-MSH and ACTH. Pigmentation protects the skin against UV-induced DNA damage and skin carcinogenesis, yet on the other hand reduces cutaneous synthesis of vitamin D. A second level of interaction may be through the ability of 1,25-dihydroxyvitamin D to increase the survival of skin cells after UV irradiation. UV irradiation-surviving cells show significant reductions in thymine dimers in the presence of 1,25-dihydroxyvitamin D that are associated with increased nuclear p53 protein expression, and significantly reduced NO products. A third level of interaction is documented by the ability of vitamin D compounds to regulate the expression of the murine double minute 2 (MDM2) gene in dependence of the presence of wild-type p53. MDM2 has a well established role as a key negative regulator of p53 activity. Finally, p53 and famil
    Frontiers in Physiology 06/2014; 5:166. DOI:10.3389/fphys.2014.00166 · 3.53 Impact Factor
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    ABSTRACT: Solar UV (UV)-B-radiation exerts both beneficial and adverse effects on human health. On the one hand, it is the most important environmental risk factor for the development of non-melanoma skin cancer [NMSC; most importantly basal (BCC) and squamous (SCC) cell carcinomas], that represent the most common malignancies in Caucasian populations. On the other hand, the human body's requirements of vitamin D are mainly achieved by UV-B-induced cutaneous photosynthesis. This dilemma represents a serious problem in many populations, for an association of vitamin D-deficiency and multiple independent diseases including various types of cancer has been convincingly demonstrated. In line with these findings, epidemiologic and laboratory investigations now indicate that vitamin D and its metabolites have a risk reducing effect for NMSC. Potential mechanisms of action include inhibition of the hedgehog signaling pathway (BCC) and modulation of p53-mediated DNA damage response (SCC). As a consequence of these new findings it can be concluded that UV-B-radiation exerts both beneficial and adverse effects on risk and prognosis of NMSC. It can be assumed that many independent factors, including frequency and dose of UV-B exposure, skin area exposed, and individual factors (such as skin type and genetic determinants of the skin`s vitamin D status and of signaling pathways that are involved in the tumorigenesis of NMSC) determine whether UV-B exposure promotes or inhibits tumorigenesis of NMSC. Moreover, these findings may help to explain many of the differential effects of UV-B radiation on risk of NMSC, including variation in the dose-dependent risk for development of SCC in situ (actinic keratosis, AK), invasive SCC, and BCC. In this review, we analyze the relevance of the vitamin D endocrine system (VDES) for tumorigenesis, prevention, and treatment of NMSC and give an overview of present concepts and future perspectives.
    Dermato-Endocrinology 01/2013; 5(1):38-50. DOI:10.4161/derm.24156
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    ABSTRACT: Vitamin D is well known for its beneficial effects on phosphocalcic homeostasis. The discovery of the role of vitamin D in cancers, infections, cardiovascular or autoimmune pathologies have promoted interest for this molecule. Skin and vitamin D are closely related. The skin is not only the site of vitamin D synthesis, but also a target organ as calcitriol plays an important hormonal and regulatory role, acting on cell proliferation, differentiation and immunomodulation. Furthermore, vitamin D influences the incidence and therapeutic response of certain dermatoses. In addition, many medical situations, mainly dermatological, require strict photoprotection and may therefore indirectly be responsible for a vitamin D deficiency in patients. The current role of vitamin D in skin cancers, inflammatory and autoimmune skin diseases is summarized.
    Revue médicale de Liège 09/2013; 68(9):458-64.
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