title: Transforming growth factor-beta 1 promotes matrix metalloproteinase-9-mediated oral cancer invasion through snail expression.
abstract: 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.
authors.affiliation: Division of Hematology/Oncology, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USA.
authors.forename: Limin
authors.initials: L
authors.lastname: Sun
authors.forename: Michelle E
authors.initials: ME
authors.lastname: Diamond
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Ottaviano
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Joseph
authors.forename: Vijayalakshmi
authors.initials: V
authors.lastname: Ananthanarayan
authors.forename: Hidayatullah G
authors.initials: HG
authors.lastname: Munshi
mesh_terms: D045744:Cell Line, Tumor; D003094:Collagen / Q000378:metabolism; D004338:Drug Combinations; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007150:Immunohistochemistry; D007797:Laminin / Q000378:metabolism; D053511:Matrix Metalloproteinase 14 / Q000378:metabolism; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism*; D009062:Mouth Neoplasms / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D009361:Neoplasm Invasiveness; D010750:Phosphoproteins / Q000378:metabolism; D011509:Proteoglycans / Q000378:metabolism; D050784:Proto-Oncogene Protein c-ets-1 / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D051899:Smad2 Protein / Q000378:metabolism; D000071250:Snail Family Transcription Factors; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000235:genetics / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology*
chemical_list: D004338:Drug Combinations; D007797:Laminin; D010750:Phosphoproteins; D011509:Proteoglycans; D050784:Proto-Oncogene Protein c-ets-1; D034741:RNA, Small Interfering; D051899:Smad2 Protein; D000071250:Snail Family Transcription Factors; D019715:Tissue Inhibitor of Metalloproteinase-1; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C059485:matrigel; D019716:Tissue Inhibitor of Metalloproteinase-2; D003094:Collagen; D020780:Matrix Metalloproteinase 9; D053511:Matrix Metalloproteinase 14