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J. Biol. Chem., Vol. 283, Issue 29, 19888-19894, July 18, 2008

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SDF-1 Promotes Invasion of Head and Neck Squamous Cell Carcinoma by Activating NF-B^*

From the Laboratory of Molecular Signaling, Division of Oral Biology and Medicine, UCLA School of Dentistry, Los Angeles, California 90095

CXCL12/stromal cell-derived factor-1 (SDF-1), a chemokine ligand for the G protein-coupled receptor CXCR4, plays an important role in the directed movement of cells. Many studies have documented the importance of CXCR4 in tumor progression and organ-specific metastasis. Recently, several studies have implicated a role for SDF-1 in head and neck squamous cell carcinoma (HNSCC) metastasis, but currently there is little information about how SDF-1 promotes HNSCC metastasis. In this report we show that the NF-B signaling pathway is activated in response to SDF-1 in HNSCC while primary and immortalized keratinocytes show no SDF-1-mediated NF-B activity. We found that SDF-1-mediated NF-B signaling is independent of phosphoinositide 3-kinase/Akt and ERK/MAPK pathways. We observed that SDF-1 induces IB phosphorylation and degradation and the nuclear translocation of NF-B in HNSCC cell lines, suggesting that SDF-1 activates the classical NF-B signaling pathway. Contrary to previous reports, SDF-1-induced NF-B activation is not mediated by tumor necrosis factor . Furthermore, blocking the NF-B signaling pathway with an IKKβ inhibitor significantly reduces SDF-1-mediated HNSCC invasion. Taken together, our data suggest SDF-1/CXCR4 may promote HNSCC invasion and metastasis by activating NF-B and that targeting NF-B may provide therapeutic opportunities in preventing HNSCC metastasis mediated by SDF-1.

Received for publication, December 21, 2007 , and in revised form, April 30, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health NIDCR Grants DE15964 and DE13848 (to C. Y. W.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ To whom correspondence should be addressed. Tel.: 310-825-4415; Fax: 310-794-7109; E-mail: cwang{at}dentistry.ucla.edu.

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