Identification and Characterization of miR-148a as a New Oncogenic and Prognostic microRNA in Glioblastoma

Abstract

Great interest persists in useful prognostic and therapeutic targets in glioblastoma (GBM), the most common and most deadly human brain tumor. In this study, we report the identification and characterization of microRNA-148a (miR-148a) as a novel prognostic oncomiR in GBM. We show that miR-148a expression is elevated in human GBM specimens, cell lines, and stem cells (GSC) compared with normal human brain and astrocytes. High levels of miR-148a were a risk indicator for GBM patient survival. Functionally, miR-148a expression increased cell growth, survival, migration, and invasion in glioblastoma cells and GSCs and promoted GSC neurosphere formation. We identified two direct targets of miR-148a, the EGF receptor (EGFR) regulator MIG6 and the apoptosis regulator BIM. Rescue experiments showed that MIG6 and BIM were essential to mediate the oncogenic activity of miR-148a. By inhibiting MIG6 expression, miR148a 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. Finally, inhibition of miR-148a strongly suppressed GSC and glioblastoma xenograft growth in vivo. Taken together, our findings provide a comprehensive analysis of the prognostic value and oncogenic function of miR-148a in glioblastoma, further defining it as a potential target for glioblastoma therapy.