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mda-9/Syntenin Regulates the Metastatic Phenotype in Human Melanoma Cells by Activating Nuclear Factor-B

Departments of ¹ Urology, ² Neurosurgery, and ³ Pathology, Herbert Irving Comprehensive Cancer Center, College of Physicians and Surgeons, Columbia University Medical Center, New York, New York

Requests for reprints: Paul B. Fisher, Departments of Pathology and Urology, College of Physicians and Surgeons, Columbia University Medical Center, 630 West 168th Street, BB-1501, New York, NY 10032. Phone: 212-305-3642, -3966; Fax: 212-305-8177; E-mail: pbf1{at}columbia.edu.

mda-9/Syntenin is a scaffolding PDZ domain-containing protein overexpressed in multiple human cancers that functions as a positive regulator of melanoma metastasis. Using a normal immortal human melanocyte cell line and weakly and highly metastatic human melanoma cell lines, we presently show that mda-9/syntenin initiates a signaling cascade that activates nuclear factor-B (NF-B) in human melanoma cells. As a consequence of elevated mda-9/syntenin expression, tumor cell growth and motility, fundamental components of tumor cell invasion and metastatic spread of melanoma cells, are enhanced through focal adhesion kinase (FAK)–induced and p38 mitogen-activated protein kinase (MAPK)–induced activation of NF-B. Inhibiting mda-9/syntenin, using an adenovirus expressing antisense mda-9/syntenin, NF-B, using an adenovirus expressing a mutant superrepressor of IB, or FAK, and using a dominant-negative mutant of FAK (FRNK), blocks melanoma cell migration, anchorage-independent growth, and invasion. Downstream signaling changes mediated by mda-9/syntenin, which include activation of FAK, p38 MAPK, and NF-B, promote induction of membrane-type matrix metalloproteinase-1 that then activates pro-MMP-2–promoting migration and extracellular matrix invasion of melanoma cells. These results highlight the importance of mda-9/syntenin as a key component of melanoma metastasis providing a rational molecular target for potentially intervening in the metastatic process. [Cancer Res 2007;67(4):1812–22]

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