The Oncogene ATF3 Is Potentiated by Cyclosporine A and Ultraviolet Light A
The Oncogene ATF3 Is Potentiated by Cyclosporine A and Ultraviolet Light A
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DOI：
10.1038/jid.2014.77
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发表时间：
2014-07-01
影响因子：
6.5
通讯作者：
Hofbauer, Guenther F. L.
中科院分区：
文献类型：
--
作者：
Dziunycz, Piotr J.;Lefort, Karine;Hofbauer, Guenther F. L.
皮肤鳞状细胞癌（SCC）是器官移植后最重要的皮肤并发症。它主要发生在阳光照射的区域。最近的一项研究表明，在用钙调磷酸酶抑制剂治疗后，激活转录因子3（ATF 3）在SCC发展中的作用。据报道，ATF 3，这可能是一个致癌基因，是负钙调磷酸酶/活化T细胞核因子（NFAT）的控制下，并上调钙调磷酸酶抑制剂。尽管如此，这些发现并不能完全解释SCC在慢性晒伤皮肤上的优先出现。我们分析了紫外线辐射对ATF 3表达的影响及其在SCC发展中的潜在作用。我们发现ATF 3是移植患者SCC中特异性诱导的AP 1成员。它的表达强烈增强环孢素A和UVA处理的组合。UVA通过活性氧介导的核因子红细胞2相关因子2（NRF 2）激活诱导ATF 3表达，与钙调神经磷酸酶/NFAT抑制无关。活化的NRF 2直接与ATF 3启动子结合，从而诱导其表达。这些结果表明，两种机制，独立地诱导，并结合在一起时，加强ATF 3的表达，这可能会迫使SCC的发展。考虑到以前定义的作用，ATF 3在SCC的发展，这些研究结果可能提供一个解释和机制，经常观察到的负担SCC的皮肤暴露区域的器官移植受者的钙调磷酸酶抑制剂治疗。
Cutaneous squamous cell carcinoma (SCC) represents the most important cutaneous complication following organ transplantation. It develops mostly on sun-exposed areas. A recent study showed the role of activating transcription factor 3 (ATF3) in SCC development following treatment with calcineurin inhibitors. It has been reported that ATF3, which may act as an oncogene, is under negative calcineurin/nuclear factor of activated T cells (NFAT) control and is upregulated by calcineurin inhibitors. Still, these findings do not fully explain the preferential appearance of SCC on chronically sun-damaged skin. We analyzed the influence of UV radiation on ATF3 expression and its potential role in SCC development. We found that ATF3 is a specifically induced AP1 member in SCC of transplanted patients. Its expression was strongly potentiated by combination of cyclosporine A and UVA treatment. UVA induced ATF3 expression through reactive oxygen species-mediated nuclear factor erythroid 2-related factor 2 (NRF2) activation independently of calcineurin/NFAT inhibition. Activated NRF2 directly binds to ATF3 promoter, thus inducing its expression. These results demonstrate two mechanisms that independently induce and, when combined together, potentiate the expression of ATF3, which may then force SCC development. Taking into account the previously defined role of ATF3 in the SCC development, these findings may provide an explanation and a mechanism for the frequently observed burden on SCCs on sunexposed areas of the skin in organ transplant recipients treated by calcineurin inhibitors.