TY - JOUR
T1 - Transforming growth factor-β1 promotes matrix metalloproteinase-9- mediated oral cancer invasion through snail expression
AU - Sun, Limin
AU - Diamond, Michelle E.
AU - Ottaviano, Adam J.
AU - Joseph, Mathew J.
AU - Ananthanarayan, Vijayalakshmi
AU - Munshi, Hidayatullah G.
PY - 2008/1/1
Y1 - 2008/1/1
N2 - 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.
AB - 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.
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U2 - 10.1158/1541-7786.MCR-07-0208
DO - 10.1158/1541-7786.MCR-07-0208
M3 - Article
C2 - 18234959
AN - SCOPUS:40749129288
SN - 1541-7786
VL - 6
SP - 10
EP - 20
JO - Molecular Cancer Research
JF - Molecular Cancer Research
IS - 1
ER -