Ultraviolet light downregulates CD95 ligand and trail receptor expression facilitating actinic keratosis and squamous cell carcinoma formation
Ultraviolet light downregulates CD95 ligand and trail receptor expression facilitating actinic keratosis and squamous cell carcinoma formation
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DOI：
10.1046/j.0022-202x.2001.01380.x
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发表时间：
2001-07-01
影响因子：
6.5
通讯作者：
Erb, P
中科院分区：
文献类型：
--
作者：
Bachmann, F;Buechner, SA;Erb, P
白种人皮肤表皮长期暴露在紫外线下与黑色素瘤和非黑色素瘤皮肤癌发生风险增加有关。紫外线辐射不仅会导致表皮细胞的DNA损伤，还会干扰皮肤的稳态，而皮肤的稳态是由诱导和阻止细胞凋亡的分子的独特分布模式维持的。我们证明，除了CD95配体外，TRAIL和TRAIL受体也在人类表皮中发挥重要的传感器作用，保持皮肤完整性并防止细胞转化。紫外线照射广泛地改变了其中一些分子的表达模式，削弱了它们的传感器功能，特别是CD95配体和TRAIL受体在紫外线照射下下调，程度较轻。CD95配体的下调不是由于蛋白质降解，原位杂交实验强烈支持转录调控。这些具有传感功能的分子的下调增加了异常细胞被较低效率消除的风险。这些分子的表达在光化性角化病中也很低或不存在，这一事实支持了这一概念，光化性角化病是由于长期紫外线照射而形成的癌前状态。浸润性肿瘤的进展伴随着CD95配体的上调和CD95和TRAIL受体的下调。CD95配体、TRAIL和FLIP在鳞状细胞癌中的高表达可能有助于肿瘤的免疫逃逸，而CD95和TRAIL受体的表达缺乏阻止肿瘤的自溶。
Long-term ultraviolet light exposure of human skin epidermis in Caucasians is associated with an increased risk for the development of melanoma and nonmelanoma skin cancers. Ultraviolet radiation not only induces DNA damage in epidermal cells, it also interferes with skin homeostasis, which is maintained by a unique distribution pattern of apoptosis-inducing and apoptosis-preventing molecules. We demonstrate that, beside CD95 ligand, TRAIL and TRAIL receptors also function as important sensors in the human epidermis preserving skin integrity and preventing cell transformation. Ultraviolet irradiation extensively changes the expression pattern of some of these molecules, diminishing their sensor function, In particular, CD95 ligand and to a somewhat lesser extent TRAIL receptors are downregulated upon ultraviolet light exposure. CD95 ligand downregulation is not due to protein degradation as in situ hybridization experiments strongly support a transcriptional regulation. The downregulation of these molecules with sensor function increases the risk that aberrant cells are less efficiently eliminated. This concept is supported by the fact that the expression of these molecules is also low or absent in actinic keratosis, a precancerous state that has developed as the consequence of long-term ultraviolet exposure. Progression to invasive neoplasms is then accompanied by an upregulation of CD95 ligand and a downregulation of CD95 and of the TRAIL receptors. The high expression of CD95 ligand, TRAIL, and FLIP in squamous cell carcinoma may then contribute to the immune escape of the tumor, whereas the lack of expression of CD95 and TRAIL receptors prevents autolysis of the tumor.