Differentiation-induced skin cancer suppression by FOS, p53, and TACE/ADAM17
Differentiation-induced skin cancer suppression by FOS, p53, and TACE/ADAM17
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DOI：
10.1172/jci63103
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发表时间：
2012-08-01
影响因子：
15.9
通讯作者：
Wagner, Erwin F.
中科院分区：
文献类型：
--
作者：
Guinea-Viniegra, Juan;Zenz, Rainer;Wagner, Erwin F.
鳞状细胞癌（SCC）是异质性和侵袭性皮肤肿瘤，需要创新的靶向治疗。在这里，我们确定了一个p53/TACE途径，负调控FOS和FOS/p53/TACE轴抑制SCC诱导分化。我们发现在小鼠肿瘤模型中表皮Fos缺失或在人SCC细胞系中药理学FOS/AP-1抑制诱导p53表达。表皮细胞分化和皮肤肿瘤抑制是由金属蛋白酶TACE/ADAM 17（TNF-α转化酶）的p53依赖性转录激活引起的，这是一种以前未知的p53靶基因，是NOTCH 1激活所必需的。尽管一半的皮肤SCC显示p53失活突变，但在小鼠和人皮肤SCC中恢复p53/TACE活性可诱导肿瘤细胞分化，而与p53状态无关。我们提出FOS/AP-1抑制或p53/TACE重新激活策略作为SCC的分化诱导疗法。
Squamous cell carcinomas (SCCs) are heterogeneous and aggressive skin tumors for which innovative, targeted therapies are needed. Here, we identify a p53/TACE pathway that is negatively regulated by FOS and show that the FOS/p53/TACE axis suppresses SCC by inducing differentiation. We found that epidermal Fos deletion in mouse tumor models or pharmacological FOS/AP-1 inhibition in human SCC cell lines induced p53 expression. Epidermal cell differentiation and skin tumor suppression were caused by a p53-dependent transcriptional activation of the metalloprotease TACE/ADAM17 (TNF-alpha-converting enzyme), a previously unknown p53 target gene that was required for NOTCH1 activation. Although half of cutaneous human SCCs display p53-inactivating mutations, restoring p53/TACE activity in mouse and human skin SCCs induced tumor cell differentiation independently of the p53 status. We propose FOS/AP-1 inhibition or p53/TACE reactivating strategies as differentiation-inducing therapies for SCCs.