7月9日，J Clin Invest.杂志在线报道了一个新的FOS负调控的p53/TACE通路，可作为鳞状细胞癌诱导分化治疗的新策略。
鳞状细胞癌（SCCs）是一种异质性和侵袭性的皮肤肿瘤有创新，需要有针对性和新颖的治疗方法。本研究发现一个FOS负调控的p53/TACE通路，而且显示，FOS/p53/TACE信号系统通过诱导分化抑制鳞状细胞癌。
研究还发现，在小鼠肿瘤模型中的表皮Fos蛋白缺失，或在人类鳞癌细胞系用药物抑制FOS/AP-1可诱导p53表达。依赖于p53的金属蛋白酶TACE/ADAM17（TNF-α转化酶）转录激活，引起表皮细胞分化并抑制皮肤肿瘤。TACE/ADAM17是一种前所未知的p53的靶基因，并为NOTCH1的激活所必需。
虽然一半的人类皮肤鳞癌存在p53基因失活突变，在小鼠和人类皮肤SCCs恢复p53/TACE可诱导不依赖于p53状态的肿瘤细胞分化。研究者提出FOS/AP-1抑制或重新激活p53/TACE作为鳞癌诱导分化疗法的策略。(生物谷bioon.com)
doi:10.1016/j.cell.2011.10.017
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Differentiation-induced skin cancer suppression by FOS, p53, and TACE/ADAM17
Juan Guinea-Viniegra1, Rainer Zenz2, Harald Scheuch3, María Jiménez1, Latifa Bakiri1, Peter Petzelbauer4 and Erwin F. Wagner
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-α–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.
