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Angiogenesis, Metastasis, and the Cellular Microenvironment

Transforming Growth Factor-β1 Promotes Matrix Metalloproteinase-9–Mediated Oral Cancer Invasion through Snail Expression

¹ Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University; ² The Jesse Brown VA Medical Center; ³ The Robert H. Lurie Comprehensive Cancer Center of Northwestern University; and ⁴ Department of Pathology, University of Illinois at Chicago, Chicago, Illinois

Requests for reprints: Hidayatullah G. Munshi, Department of Medicine, Northwestern University Medical School, 303 East Superior Avenue, Lurie 3-117, Chicago, IL 60611. Phone: 312-503-2301; Fax: 312-503-0386. E-mail: h-munshi{at}northwestern.edu

Oral squamous cell carcinoma (OSCC), which is the most common malignancy of the oral cavity, is often associated with local and regional invasion. Increased expression of matrix metalloproteinase-9 (MMP-9) is correlated with invasive behavior of OSCC. Because transforming growth factor β1 (TGF-β1) is up-regulated in OSCC tumors, we examined the relationship between TGF-β1 signaling and MMP-9 in human OSCC specimens. Evaluation of human specimens showed that tumors with enhanced TGF-β1 signaling also showed increased MMP-9 expression. Because the transcription factor Snail has been determined to be a key mediator of TGF-β1 signaling, we evaluated the role of Snail in TGF-β1–mediated MMP-9 expression. Initially, we examined the extent to which TGF-β1 regulated Snail expression in oral keratinocytes and in OSCC cell lines. TGF-β1 enhanced Snail expression in a majority of the cell lines examined, with the largest induction of Snail detected in UMSCC1 cells. Interestingly, overexpression of Snail in UMSCC1 cells enhanced MMP-9 and tissue inhibitor of metalloproteinase-1 protein levels. Despite the increase in the tissue inhibitor of metalloproteinase-1 protein, there was a net increase in the pericellular proteolytic activity as shown by enhanced MMP-9–dependent Matrigel invasion. Moreover, Snail-specific siRNA blocked TGF-β1–induced MMP-9 expression and Matrigel invasion. In addition, Snail increased Ets-1 levels and Ets-1–specific siRNA blocked both Snail- and TGF-β1–mediated MMP-9 expression and Matrigel invasion. Thus, these data show that Snail functions as a molecular mediator of TGF-β1–regulated MMP-9 expression by increasing Ets-1 and thereby contributing to oral cancer progression. (Mol Cancer Res 2008;6(1):10–20)