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Increased invasion and matrix metalloproteinase-2 expression by Snail-induced mesenchymal transition in squamous cell
Kazuhiro Yokoyama1, Nobuyuki Kamata, Ryoichi Fujimoto
1First Department of Oral and Maxillofacial Surgery, School of Dentistry, University of Tokushima, Tokushima, Japan.
Abstract:
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.
Insights
Snail triggers epithelial-mesenchymal transition (EMT), increasing cancer cell invasion. This study shows Snail upregulates matrix metalloproteinase-2 (MMP-2) expression, contributing to squamous cell carcinoma (SCC) metastasis.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Research
Background:
- Loss of E-cadherin expression is a hallmark of invasive cancers.
- Epithelial-mesenchymal transition (EMT) is linked to E-cadherin suppression and tumor progression.
- Snail, a transcription factor, induces EMT and represses E-cadherin.
Purpose of the Study:
- To investigate the role of Snail in E-cadherin suppression and cancer cell invasion.
- To determine if Snail induces EMT and upregulates matrix metalloproteinase-2 (MMP-2) in squamous cell carcinoma (SCC).
Main Methods:
- Compared E-cadherin negative and positive SCC cell lines.
- Overexpressed Snail in A431 cells to observe EMT markers (vimentin) and invasive potential.
- Utilized luciferase assays to analyze MMP-2 promoter activity in response to Snail.
Main Results:
- E-cadherin negative SCC cells exhibited fibroblastic morphology, vimentin expression, and higher invasiveness with increased MMP-2.
- Snail overexpression induced EMT, characterized by E-cadherin loss, vimentin upregulation, and increased cell invasion.
- Snail transfection upregulated MMP-2 expression and promoter activity, with a specific region (-262 to -411) being crucial for induction.
Conclusions:
- Snail acts as an inducer of MMP-2 expression in SCC.
- EMT contributes to cancer invasion by inhibiting cell-cell adhesion and upregulating MMP-2.
- Snail-induced EMT is a key mechanism driving SCC metastasis through enhanced invasion and matrix degradation.