Page 208 - Vitamin D and Cancer

9 Molecular Biology of Vitamin D Metabolism and Skin Cancer 195

9.2 The Induction of Skin Cancer by UV Radiation

Solar UV spectrum is composed of ultraviolet A (UVA) (315–400 nm), UVB
(280–315 nm) and ultraviolet C (UVC) (<280 nm). The harmful short wavelength
UVC and most of the UVB (up to 310 nm) is absorbed by the ozone layer and is
therefore not physiologically significant. On the other hand, UVA reaches the
earth’s surface and up to 50% of UVA energy penetrates to the dermis. The effects
of UVA include DNA oxidative damage, solar elastosis and skin ageing [130]. The
remaining UVB is the most energetic component of the solar UV spectrum and is
almost completely absorbed by the outer layer of the skin, the epidermis [130].
DNA is the predominant chromophore in the epidermis and absorbs most
strongly at 260 nm with decreasing absorption from the UVB to UVA spectra. The
major type of damage to DNA upon UVB absorption is the cycloaddition of the
C5–C6 double bonds of adjacent pyrimidines to cause the formation of cyclobutane
pyrimidine dimmers (CPD), e.g., thymine dimers (TD) [26, 32, 132]. If not
repaired, these can become initiating mutations in skin cancer [140] or if the DNA
damage is irreparable, the cell may undergo apoptosis [144] which is the situation
with sun burn cells. If the DNA damage escapes the gene repair system and is in a
gene involved in DNA repair, apoptosis, proliferation or cell cycle control, tumor
growth can arise [130]. In fact, in squamous cell carcinoma (SCC) and basal cell
carcinoma (BCC), the p53 gene, an essential transcription factor regulating cell
cycle control and apoptosis, bears point mutations with the features of UVB-
induced point mutations. These UVB signature mutations are C to T or CC to TT
transitions that are associated with di-pyrimidinic sites [19]. In addition, skin cells
chronically exposed to UVR may also suffer irreversible cell-mediated immunity
suppression [45], which may generate immune tolerance against immunogenic skin
tumors and exacerbate cancer outgrowth.

9.3 The Vitamin D Metabolic Pathway and Its Actions
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9.3.1 UV Radiation Induced Vitamin D Synthesis in the Skin
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Apart from the genotoxic effect of UVR, UVR also plays an important role in the
synthesis of vitamin D. The term vitamin D generally refers to two molecules, vita-
min D and D . Vitamin D is obtained through two sources. A small proportion of
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vitamin D and D can be obtained from the diet (Fig. 9.1). Vitamin D can be
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obtained from fatty fish or fish liver oil [70] while vitamin D (ergocalciferol), is the
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form of vitamin D produced by plants through the irradiation of the plant steroid,
ergosterol [116]. Majority of the vitamin D required is synthesized subcutaneously.
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The synthesis of vitamin D in human and animals begins via a photolysis reaction in
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which ultraviolet light converts 7-dehydrocholesterol (7-DHC) to previtamin D ,
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which then isomerizes to vitamin D (cholecalciferol). Both vitamin D and vitamin
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