Transforming growth factor-beta 1 promotes matrix metalloproteinase-9-mediated oral cancer invasion through snail...

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 beta1 (TGF-beta1) is up-regulated in OSCC tumors, we examined the relationship between TGF-beta1 signaling and MMP-9 in human OSCC specimens. Evaluation of human specimens showed that tumors with enhanced TGF-beta1 signaling also showed increased MMP-9 expression. Because the transcription factor Snail has been determined to be a key mediator of TGF-beta1 signaling, we evaluated the role of Snail in TGF-beta1-mediated MMP-9 expression. Initially, we examined the extent to which TGF-beta1 regulated Snail expression in oral keratinocytes and in OSCC cell lines. TGF-beta1 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-beta1-induced MMP-9 expression and Matrigel invasion. In addition, Snail increased Ets-1 levels and Ets-1-specific siRNA blocked both Snail- and TGF-beta1-mediated MMP-9 expression and Matrigel invasion. Thus, these data show that Snail functions as a molecular mediator of TGF-beta1-regulated MMP-9 expression by increasing Ets-1 and thereby contributing to oral cancer progression.