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

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 e...

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Bibliographic Details
Published in:Nucleic acids research 2013-07, Vol.41 (13), p.6618-6636
Main Authors: Zirkel, Anne, Lederer, Marcell, Stöhr, Nadine, Pazaitis, Nikolaos, Hüttelmaier, Stefan
Format: Article
Language:English
Subjects:
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
Molecular Biology
Neoplasms - pathology
Neoplasms - physiopathology
RNA-Binding Proteins - physiology
Snail Family Transcription Factors
Transcription Factors - biosynthesis
Transcription Factors - genetics
Transcription Factors - metabolism
Transcription, Genetic
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Summary: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.
ISSN:0305-1048
1362-4962
DOI:10.1093/nar/gkt410