Loss of Fas-ligand expression in mouse keratinocytes during UV carcinogenesis
Loss of Fas-ligand expression in mouse keratinocytes during UV carcinogenesis
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DOI：
10.1016/s0002-9440(10)64836-5
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发表时间：
2000-12-01
影响因子：
6
通讯作者：
Ananthaswamy, HN
中科院分区：
文献类型：
--
作者：
Ouhtit, A;Gorny, A;Ananthaswamy, HN
含有过量紫外线（UV）辐射诱导的DNA损伤的皮肤细胞通过凋亡消除，凋亡涉及p53途径和Fas/Fas-配体（Fas- l）相互作用。为了确定凋亡失调是否通过破坏Fas/Fas- l相互作用在皮肤癌的发展中起作用，将无毛SKH-hr1小鼠暴露在kodacel过滤的FS40灯的慢性紫外线照射下30周。分析他们的皮肤是否存在晒伤细胞（凋亡的角质形成细胞）。Fas和Fas- l在不同时间点的表达。早在慢性紫外线照射开始1周后，就发现形态学鉴定的晒伤细胞和tunel阳性细胞的数量急剧减少。慢性紫外线照射4周后，这些细胞几乎检测不到。这种凋亡缺陷与慢性紫外线照射第一周Fas-L表达的初始降低和4周后完全丧失表达相平行。然而，在慢性紫外线暴露过程中，Fas表达增加。早在照射开始后1周，就在紫外线照射的表皮中检测到p53突变，并随着进一步的紫外线照射继续积累。暴露于慢性紫外线下的小鼠在大约8周后开始出现皮肤肿瘤，到24周时所有小鼠都出现了多发性皮肤肿瘤。大部分肿瘤表达Fas，但不表达Fas- l。我们得出的结论是，长期暴露在紫外线下可能会导致Fas-L表达的丧失和p53突变的增加，导致细胞凋亡的失调，角化细胞突变的扩大，并引发皮肤癌。
Skin cells containing excessive ultraviolet (UV) radiation-induced DNA damage are eliminated by apoptosis that involves the p53 pathway and Fas/Fas-Ligand (Fas-L) interactions. To determine whether dysregulation of apoptosis plays a role in skin cancer development through disruption of Fas/Fas-L interactions, hairless SKH-hr1 mice were exposed to chronic UV irradiation from Kodacel-filtered FS40 lamps for 30 weeks. Their skin was analyzed for the presence of sunburn cells (apoptotic keratinocytes) and. for Fas and Fas-L expression at various time points. A dramatic decrease in the numbers of morphologically identified sunburn cells and TUNEL-positive cells was detected as early as 1 week after chronic UV exposure began. After 4 weeks of chronic UV exposure, these cells were barely detectable. This defect in apoptosis was paralleled by an initial decrease in Fas-L expression during the first week of chronic UV irradiation and a complete loss of expression after 4 weeks. Fas expression, however, increased during the course of chronic UV exposure.p53 mutations were detected in the UV-irradiated epidermis as early as 1 week after irradiation began and continued to accumulate with further UV exposure. Mice exposed to chronic UV began to develop skin tumors after approximately 8 weeks, and all mice had multiple skin tumors by 24 weeks. Most of the tumors expressed Fas but not Fas-L. We conclude that chronic UV exposure may induce a loss of Fas-L expression and a gain in p53 mutations, leading to dysregulation of apoptosis, expansion of mutated keratinocytes,and initiation of skin cancer.