IGF2BP1 promotes mesenchymal cell properties and migration of tumor-derived cells by enhancing the expression of LEF1 and SNAI2 (SLUG)

Nucleic Acids Res. 2013 Jul;41(13):6618-36. doi: 10.1093/nar/gkt410. Epub 2013 May 15.

Abstract

The oncofetal IGF2 mRNA-binding protein 1 (IGF2BP1) controls the migration and invasiveness of primary as well as tumor-derived cells in vitro. Whether the protein also modulates epithelial-mesenchymal-transition (EMT), a hallmark of tumor progression involved in tumor cell dissemination, remained elusive. In this study, we reveal that IGF2BP1 enhances mesenchymal-like cell properties in tumor-derived cells by promoting the expression of the transcriptional regulators LEF1 and SLUG (SNAI2). IGF2BP1 associates with LEF1 transcripts and prevents their degradation in a 3'-UTR-dependent manner resulting in an upregulation of LEF1 expression. LEF1 promotes transcription of the mesenchymal marker fibronectin by associating with the fibronectin 1 promoter. Moreover, LEF1 enforces the synthesis of the 'EMT-driving' transcriptional regulator SNAI2. Accordingly, IGF2BP1 knockdown causes MET-like (mesenchymal-epithelial-transition) morphological changes, enhances the formation of cell-cell contacts and reduces cell migration in various mesenchymal-like tumor-derived cells. However, in epithelial-like tumor-derived cells characterized by a lack or low abundance of IGF2BP1, the protein fails to induce EMT. These findings identify IGF2BP1 as a pro-mesenchymal post-transcriptional determinant, which sustains the synthesis of 'EMT-driving' transcriptional regulators, mesenchymal markers and enhances tumor cell motility. This supports previous reports, suggesting a role of IGF2BP1 in tumor cell dissemination.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cell Line, Tumor
  • Cell Movement*
  • Epithelial-Mesenchymal Transition*
  • Fibronectins / biosynthesis
  • Fibronectins / genetics
  • HEK293 Cells
  • Humans
  • Lymphoid Enhancer-Binding Factor 1 / genetics
  • Lymphoid Enhancer-Binding Factor 1 / metabolism*
  • Mesoderm / cytology*
  • Neoplasms / pathology
  • Neoplasms / physiopathology*
  • RNA-Binding Proteins / physiology*
  • Snail Family Transcription Factors
  • Transcription Factors / biosynthesis
  • Transcription Factors / genetics
  • Transcription Factors / metabolism*
  • Transcription, Genetic

Substances

  • FN1 protein, human
  • Fibronectins
  • IGF2BP1 protein, human
  • LEF1 protein, human
  • Lymphoid Enhancer-Binding Factor 1
  • RNA-Binding Proteins
  • SNAI1 protein, human
  • SNAI2 protein, human
  • Snail Family Transcription Factors
  • Transcription Factors