Tumor necrosis factor receptor 1/c-Jun-NH2-kinase signaling promotes human neoplasia.
Tumor necrosis factor receptor 1/c-Jun-NH2-kinase signaling promotes human neoplasia.
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DOI：
10.1158/0008-5472.can-06-4017
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发表时间：
2007-04
期刊：
影响因子：
11.2
通讯作者：
Jennifer Y. Zhang;A. E. Adams;T. Ridky;Shiying Tao;P. Khavari
中科院分区：
文献类型：
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作者：
Jennifer Y. Zhang;A. E. Adams;T. Ridky;Shiying Tao;P. Khavari
肿瘤坏死因子α受体（TNFR1）激活下游效应物，包括丝裂原活化蛋白激酶激酶7 (MKK7)/c-Jun-NH(2)-激酶(JNK)/激活蛋白1 （AP1）级联。在这里，我们报告了JNK在大多数自发性人类鳞状细胞癌（SCC）中被激活。JNK通路的诱导绕过了致癌Ras诱导的细胞周期限制，并与Ras合作将正常的人表皮转化为与SCC没有区别的肿瘤，证实了其在人体组织中的致癌效力。通过遗传、药理学或抗体介导的方法抑制MKK7、JNK和AP1以及TNFR1本身，以肿瘤细胞自主的方式消除侵袭性人表皮肿瘤。因此，TNFR1/MKK7/JNK/AP1级联促进人类肿瘤形成，代表了人类上皮癌的潜在治疗靶点。
The tumor necrosis factor alpha receptor (TNFR1) activates downstream effectors that include the mitogen-activated protein kinase kinase 7 (MKK7)/c-Jun-NH(2)-kinase (JNK)/activator protein 1 (AP1) cascade. Here, we report that JNK is activated in a majority of spontaneous human squamous cell carcinomas (SCC). JNK pathway induction bypassed cell cycle restraints induced by oncogenic Ras and cooperated with Ras to convert normal human epidermis into tumors indistinguishable from SCC, confirming its oncogenic potency in human tissue. Inhibiting MKK7, JNK, and AP1 as well as TNFR1 itself using genetic, pharmacologic, or antibody-mediated approaches abolished invasive human epidermal neoplasia in a tumor cell autonomous fashion. The TNFR1/MKK7/JNK/AP1 cascade thus promotes human neoplasia and represents a potential therapeutic target for human epithelial cancers.