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Tumor Necrosis Factor Receptor 1/c-Jun-NH₂-Kinase Signaling Promotes Human Neoplasia

¹ Department of Medicine, Division of Dermatology, Duke University School of Medicine, Durham, North Carolina and ² Program in Epithelial Biology, Stanford University School of Medicine, Stanford, California

Requests for reprints: Jennifer Y. Zhang, Duke Hospital South, Room 4041, Purple Zone, Trent Drive, Durham, NC 27710. Phone: 919-684-6794; Fax: 919-684-3002; E-mail: Jennifer.zhang{at}duke.edu or Paul A. Khavari, Program in Epithelial Biology, Stanford University School of Medicine, Room 2145, 269 Campus Drive, Stanford, CA 94305. Phone: 650-725-5266; Fax: 650-723-8762; E-mail: khavari{at}cmgm.stanford.edu.

The tumor necrosis factor receptor (TNFR1) activates downstream effectors that include the mitogen-activated protein kinase kinase 7 (MKK7)/c-Jun-NH₂-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. [Cancer Res 2007;67(8):3827–34]