Abstract
Ultraviolet (UV) radiation is involved in almost all skin cancer cases, but on the other hand, it stimulates the production of pre-vitamin D3, whose active metabolite, 1,25-dihydroxyvitamin D3 (1,25VD3), plays important physiological functions on binding with its receptor (vitamin D receptor, VDR). UV-induced DNA damages in the form of cyclobutane pyrimidine dimers or (6-4)-pyrimidine-pyrimidone photoproducts are frequently found in skin cancer and its precursors. Therefore, removing these lesions is essential for the prevention of skin cancer. As UV-induced DNA damages are repaired by nucleotide excision repair (NER), the interaction of 1,25VD3 with NER components can be important for skin cancer transformation. Several studies show that 1,25VD3 protects DNA against damage induced by UV, but the exact mechanism of this protection is not completely clear. 1,25VD3 was also shown to affect cell cycle regulation and apoptosis in several signaling pathways, so it can be considered as a potential modulator of the cellular DNA damage response, which is crucial for mutagenesis and cancer transformation. 1,25VD3 was shown to affect DNA repair and potentially NER through decreasing nitrosylation of DNA repair enzymes by NO overproduction by UV, but other mechanisms of the interaction between 1,25VD3 and NER machinery also are suggested. Therefore, the array of NER gene functioning could be analyzed and an appropriate amount of 1.25VD3 could be recommended to decrease UV-induced DNA damage important for skin cancer transformation.
Highlights
Skin cancer belongs to the most common human malignancies, with the highest rate of incidence in Caucasians [1]
Some non-genomic actions of 1,25VD3 occur through membrane-anchored vitamin D receptors, as 1,25-dihydroxyvitamin D3-membrane associated rapid response steroid binding (MARRS) [36]
UV radiation can block the activity of PTPRK enabling phosphorylation of epidermal growth factor receptor (EGFR), transforming it in its active form, which can play an important role in skin carcinogenesis
Summary
Skin cancer belongs to the most common human malignancies, with the highest rate of incidence in Caucasians [1]. Non-melanoma skin cancers (NMSCs) can be categorized into two types, depending on their origin—basal cell carcinomas (BCCs), and squamous cell carcinomas (SCCs) [1]. It is transported to the liver and undergoes hydroxylation to 25-hydroxyvitamin D3 (25D), which is the major circulating form of vitamin D3 [19] This hydroxylation is carried out by four cytochrome P-450 enzymes, three microsomal—CYP2R1, CYP2J2 and CYP3A4, and one mitochondrial, CYP27A1 [20,21]. Some non-genomic actions of 1,25VD3 occur through membrane-anchored vitamin D receptors, as 1,25-dihydroxyvitamin D3-membrane associated rapid response steroid binding (MARRS) [36]. The VDR gene is under the control of four promoters, which are tissue-specific and multiple alternative isoforms can be generated from them
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