Increased invasion and matrix metalloproteinase-2 expression by Snail-induced mesenchymal transition in squamous cell carcinomas.
Loss of E-cadherin expression is a major characteristic of highly invasive and metastatic cancers. Epithelial-mesenchymal transition (EMT) has been advocated to be a causative mechanism for the suppression of E-cadherin and tumor progression. Snail is a zinc finger transcription factor that triggers the EMT and is one of the recently identified E-cadherin repressors. The reverse correlation of Snail and E-cadherin expressions has been reported in many types of human cancers including squamous cell carcinoma (SCC). In this study, we showed that three E-cadherin negative SCC cell lines had a fibroblastic morphology, strong expressions of vimentin, a mesenchymal marker gene, and Snail. Compared to other E-cadherin positive SCC cells, these cells showed higher invasive ability and expression of MMP-2, a matrix degrading enzyme which has been demonstrated to be highly expressed in invasive cancer cells. Over-expression of Snail in A431 cells resulted in the loss of E-cadherin expression, the change of their morphology to fibroblastic, and the up-regulation of vimentin gene expression, indicating that an EMT was induced by Snail. Furthermore, these cells became more invasive and showed higher levels of MMP-2 activity and its gene expression. Luciferase analysis demonstrated that the MMP-2 promoter activity was induced by Snail transfection and the promoter region from -262 to -411 relative to the transcriptional start site was necessary for this induction. These results indicate that Snail is a new inducer of MMP-2 expression and suggest that the EMT contributes to the increased invasion not only through the inhibition of cell-cell adhesion but also the up-regulation of MMP-2 expression in SCC cells.
Yokoyama
Kazuhiro
K
First Department of Oral and Maxillofacial Surgery, School of Dentistry, University of Tokushima, Tokushima, Japan.
Kamata
Nobuyuki
N
Fujimoto
Ryoichi
R
Tsutsumi
Satoshi
S
Tomonari
Mayumi
M
Taki
Masayuki
M
Hosokawa
Hiroyoshi
H
Nagayama
Masaru
M
D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism*; D002448:Cell Adhesion; D002460:Cell Line; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000378:metabolism*; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008156:Luciferases / Q000378:metabolism; D020778:Matrix Metalloproteinase 2 / Q000096:biosynthesis* / Q000378:metabolism*; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors / Q000378:metabolism*; D014158:Transcription, Genetic; D014162:Transfection; D015854:Up-Regulation; D014746:Vimentin / Q000096:biosynthesis; D015032:Zinc / Q000378:metabolism
D015820:Cadherins; D004268:DNA-Binding Proteins; D012333:RNA, Messenger; D000071250:Snail Family Transcription Factors; D014157:Transcription Factors; D014746:Vimentin; D008156:Luciferases; D020778:Matrix Metalloproteinase 2; D015032:Zinc