Increased invasion and matrix metalloproteinase-2 expression by Snail-induced mesenchymal transition in squamous cell carcinomas

Int J Oncol. 2003 Apr;22(4):891-8.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Blotting, Western
  • Cadherins / metabolism
  • Carcinoma, Squamous Cell / metabolism*
  • Cell Adhesion
  • Cell Line
  • Cell Line, Tumor
  • DNA-Binding Proteins / metabolism*
  • Disease Progression
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Luciferases / metabolism
  • Matrix Metalloproteinase 2 / biosynthesis*
  • Matrix Metalloproteinase 2 / metabolism*
  • Neoplasm Invasiveness
  • Phenotype
  • Promoter Regions, Genetic
  • RNA, Messenger / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Snail Family Transcription Factors
  • Transcription Factors / metabolism*
  • Transcription, Genetic
  • Transfection
  • Up-Regulation
  • Vimentin / biosynthesis
  • Zinc / metabolism

Substances

  • Cadherins
  • DNA-Binding Proteins
  • RNA, Messenger
  • Snail Family Transcription Factors
  • Transcription Factors
  • Vimentin
  • Luciferases
  • Matrix Metalloproteinase 2
  • Zinc