microRNA-148a is a prognostic oncomiR that targets MIG6 and BIM to regulate EGFR and apoptosis in glioblastoma
A partir de données portant sur l'expression du micro-ARN 148a dans des échantillons de glioblastome, des lignées cellulaires et des cellules souches, puis in vitro et à l'aide de xénogreffes, cette étude suggère l'iintérêt de mesurer l'expression de ce micro-ARN pour le pronostic de la maladie
Great interest persists in useful prognostic and therapeutic targets in glioblastoma (GBM). In this study, we report the definition of miR-148a as a novel prognostic oncomiR in GBM. miR-148a expression was elevated in human GBM specimens, cell lines and stem cells (GSCs) compared to normal human brain and astrocytes. High levels were a risk indicator for GBM patient survival. Functionally, miR-148a expression increased cell growth, survival, migration, and invasion in GBM cells and GSCs and promoted GSC neurosphere formation. Two direct targets of miR-148a were identified, the EGFR regulator MIG6 and the apoptosis regulator BIM, which rescue experiments showed were essential to mediate the oncogenic activity of miR-148a. By inhibiting MIG6 expression, miR-148a reduced EGFR trafficking to Rab7-expressing compartments which includes late endosomes and lysosomes. This process coincided with reduced degradation and elevated expression and activation of EGFR. Lastly, inhibition of miR-148a strongly suppressed GSC and GBM xenograft growth in vivo. Taken together, our findings provide a comprehensive analysis of the prognostic value and oncogenic function of miR-148a in GBM, and further defining it as a potential target for GBM therapy.
Cancer Research , résumé, 2014