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.
Highlights
Epithelial-mesenchymal-transition (EMT) is essential during embryogenesis and is considered a hallmark in the progression of carcinomas [reviewed in [1,2]]
Aiming to reveal whether IGF2 mRNA-binding protein 1 (IGF2BP1) modulates mesenchymal versus epithelial cell properties, we analyzed its role in transformed embryonic kidney-derived 293 A (HEK293) cells
Of all three factors caused severe morphological changes in HT-144 with an increase of CTNNB1 positive cell–cell contact sites (Figure 6E and F). These findings indicated that IGF2BP1 sustains the expression of mesenchymal markers and mesenchymal-like cell morphology involving the enhancement of LEF1 and SNAI2 expression
Summary
Epithelial-mesenchymal-transition (EMT) is essential during embryogenesis and is considered a hallmark in the progression of carcinomas [reviewed in [1,2]]. Accumulating evidence indicates that the post-transcriptional control of gene expression facilitated by microRNAs essentially modulates EMT and its reversal, mesenchymal-epithelial-transition (MET). One of the most studied post-transcriptional mechanisms promoting EMT is facilitated via the miR200 family. This antagonizes TGF-b (TGFB)-induced EMT by interfering with the expression of ZEBs, two key transcriptional repressors of E-cadherin (CDH1) [reviewed in [3]]. Another double-negative feedback loop modulating cell plasticity essentially relies on the miR-34 family, which links p53 signaling and negative regulation of Snail (SNAI1) expression, another ‘EMT-driving’ transcriptional regulator [4,5]. It was demonstrated that La enhances the IRES-mediated translation of the extracellular matrix protein laminin B1 during malignant EMT [7]
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