7月9日,，J Clin Invest.雜志在線報道了一個新的FOS負調控的p53/TACE通路，可作為鱗狀細胞癌誘導分化治療的新策略,。
鱗狀細胞癌（SCCs）是一種異質性和侵襲性的皮膚腫瘤有創(chuàng)新,，需要有針對性和新穎的治療方法。本研究發(fā)現(xiàn)一個FOS負調控的p53/TACE通路,，而且顯示,，F(xiàn)OS/p53/TACE信號系統(tǒng)通過誘導分化抑制鱗狀細胞癌。
研究還發(fā)現(xiàn),，在小鼠腫瘤模型中的表皮Fos蛋白缺失,，或在人類鱗癌細胞系用藥物抑制FOS/AP-1可誘導p53表達。依賴于p53的金屬蛋白酶TACE/ADAM17（TNF-α轉化酶）轉錄激活,，引起表皮細胞分化并抑制皮膚腫瘤,。TACE/ADAM17是一種前所未知的p53的靶基因，并為NOTCH1的激活所必需,。
雖然一半的人類皮膚鱗癌存在p53基因失活突變,，在小鼠和人類皮膚SCCs恢復p53/TACE可誘導不依賴于p53狀態(tài)的腫瘤細胞分化。研究者提出FOS/AP-1抑制或重新激活p53/TACE作為鱗癌誘導分化療法的策略,。(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.
