1α,25(OH)2-Vitamin D and a Nongenomic Vitamin D Analogue Inhibit Ultraviolet Radiation-Induced Skin Carcinogenesis
1α,25(OH)2-Vitamin D and a Nongenomic Vitamin D Analogue Inhibit Ultraviolet Radiation-Induced Skin Carcinogenesis
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DOI：
10.1158/1940-6207.capr-11-0165
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发表时间：
2011-09-01
影响因子：
3.3
通讯作者：
Mason, Rebecca S.
中科院分区：
文献类型：
--
作者：
Dixon, Katie M.;Norman, Anthony W.;Mason, Rebecca S.
暴露于紫外线辐射 (UVR) 会导致皮肤产生一系列有害反应。一种重要的损伤形式是 DNA 光损伤环丁烷嘧啶二聚体 (CPD)。如果在细胞分裂前未修复，CPD 可能具有高度诱变性，并可能导致紫外线诱导的免疫抑制，从而具有潜在的致癌性。紫外线照射还会产生维生素 D（一种前激素）。不同形状的类固醇激素 1 α,25-二羟基维生素 D-3 [1,25(OH)(2)D-3] 可以通过与其同源核受体 (VDR) 结合来调节基因转录，或与质膜小窝相关的 VDR 结合，通过信号转导产生非基因组生理反应，从而产生生物反应。在这里，我们表明，1,25(OH)(2)D-3 和 1 α,25(OH)(2)-lumisterol (JN)（一种只能产生非基因组反应的构象限制类似物）是易受紫外线诱导肿瘤影响的免疫活性小鼠 (Skh:hr1) 模型中紫外线损伤的有效抑制剂。 1,25(OH)(2)D-3 和 JN 均显着减少 UVR 诱导的 CPD、凋亡晒伤细胞和免疫抑制。此外，这些化合物抑制了这些小鼠的皮肤肿瘤的发展，包括乳头状瘤和鳞状细胞癌。观察到 1,25 (OH)(2)D-3 和 JN 可减少这些紫外线引起的影响，表明这些化合物在预防皮肤癌方面具有作用。据我们所知，这是第一份关于长期服用非基因组选择性维生素 D 类固醇所产生的体内长期生物反应的综合报告。癌症预防研究； 4（9）； 1485-94。 (C) 2011 年 AACR。
Exposure to ultraviolet radiation (UVR) can lead to a range of deleterious responses in the skin. An important form of damage is the DNA photolesion cyclobutane pyrimidine dimer (CPD). CPDs can be highly mutagenic if not repaired prior to cell division and can lead to UV-induced immunosuppression, making them potentially carcinogenic. UVR exposure also produces vitamin D, a prehormone. Different shapes of the steroid hormone 1 alpha,25-dihydroxyvitamin D-3 [1,25(OH)(2)D-3] can produce biological responses through binding either to its cognate nuclear receptor (VDR) to regulate gene transcription or to the VDR associated with plasma membrane caveolae to produce, via signal transduction, nongenomic physiologic responses. Here, we show that both 1,25(OH)(2)D-3 and 1 alpha,25(OH)(2)-lumisterol (JN), a conformationally restricted analogue that can generate only nongenomic responses, are effective inhibitors of UV damage in an immunocompetent mouse (Skh:hr1) model susceptible to UV-induced tumors. Both 1,25(OH)(2)D-3 and JN significantly reduced UVR-induced CPD, apoptotic sunburn cells, and immunosuppression. Furthermore, these compounds inhibited skin tumor development, both papillomas and squamous cell carcinomas, in these mice. The observed reduction of these UV-induced effects by 1,25 (OH)(2)D-3 and JN suggests a role for these compounds in prevention against skin carcinogenesis. To the best of our knowledge, this is the first comprehensive report of an in vivo long-term biological response generated by chronic dosing with a nongenomic-selective vitamin D steroid. Cancer Prev Res; 4(9); 1485-94. (C) 2011 AACR.