Involvement of Ets-1 transcription factor in inducing matrix metalloproteinase-2 expression by epithelial-mesenchymal transition in human squamous carcinoma cells.
Epithelial-mesenchymal transition (EMT) is a crucial event in cancer progression. We previously reported that EMT up-regulates matrix metalloproteinase-2 (MMP-2) expression in squamous cell carcinoma (SCC) cells. In this study, we showed that Tet Off-induced expression of Snail or SIP1, and treatment with TGF-beta1 induced EMT in terms of down-regulation of E-cadherin, and up-regulation of vimentin and MMP-2 expression with morphological changes. In SCC cells, SIP1 expression was induced by Snail and TGF-beta1, but Snail expression was not induced by SIP1 or TGF-beta1. However, expression of Snail but not SIP1 was strongly increased by TGF-beta1 in highly invasive SCC cells with mesenchymal phenotypes. Analysis of the MMP-2 promoter revealed that an Ets-1 binding site, located between position -1255 and -1248 relative to the transcriptional start site, was critical for the activation by Snail, SIP1 and TGF-beta1 in SCC cells. Induced expression of Snail and SIP1 resulted in the increased expression of Ets-1 and DNA-binding activities of nuclear proteins to the Ets-1-binding site and strong Ets-1 expression was detected in highly invasive SCC cells. Furthermore, overexpression of Ets-1 induced the promoter-activation and expression of MMP-2 without EMT. These results indicate that EMT induces Ets-1 expression, which activates the MMP-2 promoter, but Ets-1 by itself has no activity to induce EMT in SCC cells.
Taki
Masayuki
M
Department of Oral and Maxillofacial Surgery, Division of Cervico-Gnathostomatology, Graduate School of Biomedical Sciences, Hiroshima University, Minami-ku, Hiroshima 734-8553, Japan.
Verschueren
Kristin
K
Yokoyama
Kazuhiro
K
Nagayama
Masaru
M
Kamata
Nobuyuki
N
D015820:Cadherins / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects*; D018398:Homeodomain Proteins / Q000096:biosynthesis / Q000235:genetics; D006801:Humans; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000235:genetics; D008648:Mesoderm / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D011401:Promoter Regions, Genetic; D050784:Proto-Oncogene Protein c-ets-1 / Q000235:genetics / Q000378:metabolism*; D012333:RNA, Messenger / Q000378:metabolism; D012097:Repressor Proteins / Q000096:biosynthesis / Q000235:genetics; D000071250:Snail Family Transcription Factors; D013997:Time Factors; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D000074165:Zinc Finger E-box Binding Homeobox 2
D015820:Cadherins; D018398:Homeodomain Proteins; D050784:Proto-Oncogene Protein c-ets-1; D012333:RNA, Messenger; D012097:Repressor Proteins; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D053773:Transforming Growth Factor beta1; C492363:ZEB2 protein, human; D000074165:Zinc Finger E-box Binding Homeobox 2; D020778:Matrix Metalloproteinase 2