Tumor suppressor miR-181c attenuates proliferation, invasion, and self-renewal abilities in glioblastoma.

Abstract

Glioblastoma multiforme (GBM) is well known for its aggressiveness, but the underlying mechanisms are unclear, limiting the treatment. In the present study, we showed that miR-181c, a commonly downregulated miRNA in GBM reported by several miRNA profiles, was associated with the mesenchymal subtype of GBM and predicted the outcome for patients from a GBM cohort (n=518) obtained from The Cancer Genome Atlas database. A multivariate analysis showed that miR-181c was an independent prognostic indicator for GBM patients. Quantitative reverse transcription PCR showed that miR-181c was expressed poorly in neurospheres of glioma cells that resemble glioma stem cells. Proliferation and invasion assays showed that miR-181c also blocked the proliferation and invasion abilities of glioma cells. Limiting dilution and colony formation assays showed that miR-181c attenuated the self-renewal ability of glioma cells. Finally, investigation of the mechanism defined Notch2, a key molecular of Notch signaling, as the functional downstream target of miR-181c. An inverse correlation was found between miR-181c and Notch2 in glioma cells and verified in fresh glioma samples. Taken together, the present study showed that miR-181c can be considered a valuable indicator for the outcome of GBM patients. miR-181c acts as a tumor suppressor that attenuates proliferation, invasion, and self-renewal capacities by downregulation of Notch2 in glioma cells.