Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management.
Vitamin D signaling and melanoma: role of vitamin D and its receptors in melanoma progression and management.
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DOI：
10.1038/labinvest.2017.3
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发表时间：
2017-06
期刊：
影响因子：
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通讯作者：
Elmets CA
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作者：
Slominski AT;Brożyna AA;Zmijewski MA;Jóźwicki W;Jetten AM;Mason RS;Tuckey RC;Elmets CA
紫外线B（UVB）除了具有致癌活性外，还需要在皮肤中产生维生素D3（D3），提供人体90%以上的需求。维生素D通过25-羟化酶（CYP 2 R1或CYP 27 A1）和1α-羟化酶（CYP 27 B1）的羟基化作用活化，产生1，25（OH）2D 3，或通过CYP 11 A1的作用产生单、二和三羟基-D3产物，这些产物可被CYP 27 B1、CYP 27 A1和CYP 24 A1进一步修饰。活性形式的D3，除了调节钙代谢，发挥多效性活动，其中包括抗癌和抗黑色素瘤的作用，在实验模型中，与光保护对UVB诱导的损伤。这些不同的作用通过与维生素D受体（VDR）的相互作用介导，和/或最近通过对维甲酸孤儿受体（ROR）α和RORγ的作用证实。对于黑色素瘤，低水平的25（OH）D与较厚的肿瘤和患者生存率降低有关。此外，VDR和维生素D结合蛋白（VDP）基因的单核苷酸多态性影响黑色素瘤的发生或疾病的结果。临床病理学分析显示，黑色素瘤中VDR和/或CYP 27 B1的低表达或检测不到表达与肿瘤进展和较短的总（OS）和无病生存（DFS）时间呈正相关。有趣的是，这种相关性在CYP 24 A1（灭活24-羟化酶）中被逆转，表明这种酶在灭活1，25（OH）2D 3的同时，可以激活其他形式的D3，这些D3是由CYP 11 A1启动的非经典途径的产物。已发现RORα和RORγ表达水平与黑色素瘤进展和疾病结局之间呈负相关。因此，我们认为维生素D信号传导（包括D3激活/失活）的缺陷以及相应受体的表达和活性会影响黑色素瘤的进展和疾病的结局。当应用维生素D管理治疗黑色素瘤时，应考虑到存在多种生物活性形式的D3和影响黑色素瘤行为的替代受体。
Ultraviolet B (UVB), in addition to having carcinogenic activity, is required for the production of vitamin D3 (D3) in the skin which supplies >90% of the body's requirement. Vitamin D is activated through hydroxylation by 25-hydroxylases (CYP2R1 or CYP27A1) and 1α-hydroxylase (CYP27B1) to produce 1,25(OH)2D3, or through the action of CYP11A1 to produce mono-di- and trihydroxy-D3 products that can be further modified by CYP27B1, CYP27A1, and CYP24A1. The active forms of D3, in addition to regulating calcium metabolism, exert pleiotropic activities, which include anticarcinogenic and anti-melanoma effects in experimental models, with photoprotection against UVB-induced damage. These diverse effects are mediated through an interaction with the vitamin D receptor (VDR) and/or as most recently demonstrated through action on retinoic acid orphan receptors (ROR)α and RORγ. With respect to melanoma, low levels of 25(OH)D are associated with thicker tumors and reduced patient survival. Furthermore, single-nucleotide polymorphisms of VDR and the vitamin D-binding protein (VDP) genes affect melanomagenesis or disease outcome. Clinicopathological analyses have shown positive correlation between low or undetectable expression of VDR and/or CYP27B1 in melanoma with tumor progression and shorter overall (OS) and disease-free survival (DFS) times. Paradoxically, this correlation was reversed for CYP24A1 (inactivating 24-hydroxylase), indicating that this enzyme, while inactivating 1,25(OH)2D3, can activate other forms of D3 that are products of the non-canonical pathway initiated by CYP11A1. An inverse correlation has been found between the levels of RORα and RORγ expression and melanoma progression and disease outcome. Therefore, we propose that defects in vitamin D signaling including D3 activation/inactivation, and the expression and activity of the corresponding receptors, affect melanoma progression and the outcome of the disease. The existence of multiple bioactive forms of D3 and alternative receptors affecting the behavior of melanoma should be taken into consideration when applying vitamin D management for melanoma therapy.