The RNA Binding Protein IMP2 Preserves Glioblastoma Stem Cells by Preventing let-7 Target Gene Silencing.

Ivan Stamenkovic,Renato Paro,Patricia Martin,Mario-L. Suvà,Tommy B. Schlumpf,Nicolo Riggi,Nils Degrauwe,Alexandra Cauderay,Paolo Provero,Michalina Janiszewska

doi:10.1016/j.celrep.2016.04.086

Abstract

Cancer stem cells (CSCs) can drive tumor growth, and their maintenance may rely on post-transcriptional regulation of gene expression, including that mediated by microRNAs (miRNAs). The let-7 miRNA family has been shown to induce differentiation by silencing stem cell programs. Let-7-mediated target gene suppression is prevented by LIN28A/B, which reduce let-7 biogenesis in normal embryonic and some cancer stem cells and ensure maintenance ofstemness. Here, we find that glioblastoma stem cells (GSCs) lack LIN28 and express both let-7 and their target genes, suggesting LIN28-independent protection from let-7 silencing. Using photoactivatable-ribonucleoside-enhanced crosslinking and immunoprecipitation (PAR-CLIP), we show that insulin-like growth factor 2 mRNA-binding protein 2 (IMP2) binds to let-7 miRNA recognition elements (MREs) and prevents let-7 target gene silencing. Our observations define the RNA-binding repertoire of IMP2 and identify a mechanism whereby it supports GSC and neural stem cell specification.

Highlights

Glioblastoma (GBM) is the most common and the most lethal primary brain malignancy in adults, with a 5-year survival rate below 5%, despite aggressive multimodal therapy
Cancer stem cells (CSCs) can drive tumor growth, and their maintenance may rely on post-transcriptional regulation of gene expression, including that mediated by microRNAs
Let-7-mediated target gene suppression is prevented by LIN28A/B, which reduce let-7 biogenesis in normal embryonic and some cancer stem cells and ensure maintenance of stemness

Summary

Introduction

Glioblastoma (GBM) is the most common and the most lethal primary brain malignancy in adults, with a 5-year survival rate below 5%, despite aggressive multimodal therapy. Glioblastoma contains highly plastic subpopulations of cells that are capable of self-renewal, tumor initiation, and differentiation into cells that constitute the tumor bulk, consistent with the functional definition of cancer stem cells (CSCs) (Kreso and Dick, 2014). These cells are commonly referred to as glioma stem cells (GSCs) and are thought to bear the principal responsibility for resistance to therapy and relapse (Singh et al, 2003; Chen et al, 2012; Bao et al, 2006). The same mechanisms are believed to be responsible for the reprogramming that

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Discussion

Conclusion