Upregulation of miR-181a suppresses the formation of glioblastoma stem cells by targeting the Notch2 oncogene and correlates with good prognosis in patients with glioblastoma multiforme.

Glioblastoma stem-like cells (GSCs) are responsible for the initiation and progression of glioblastoma multiforme (GBM), and microRNAs (miRNAs) play an important role in this disease. However, the mechanisms underlying the role of miRNAs in the stemness of GSCs have not been completely elucidated. We previously showed that miR-181a is downregulated in GBM and may predict prognosis in patients with this disease. Here, we demonstrate that the upregulation of miR-181a suppressed GSC formation and inhibited GBM tumorigenesis by targeting the Notch2 oncogene. We found that miR-181a was downregulated in GSCs derived from human glioblastoma U87MG and U373MG cells. The high expression of miR-181a inhibited the levels of stemness-related markers CD133 and BMI1, attenuated sphere proliferation, promoted cell apoptosis, and reduced the tumorigenicity of GSCs. MiR-181a decreased the expression of Notch2 by targeting the 3'-untranslated region of its mRNA. Notch2 overexpression inhibited the effects of miR-181a downregulation on GSCs, and was negatively correlated with miR-181a expression. Moreover, high Notch2 expression together with low miR-181a expression was correlated with a shorter median overall survival for GBM patients. Together, these data show that miR-181a may play an essential role in GSC formation and GBM progression by targeting Notch2, suggesting that Notch2 and miR-181a have potential prognostic value as tumor biomarkers in GBM patients.

The correlation of microRNA-181a and target genes with poor prognosis of glioblastoma patients.

To investigate the expression and clinical significance of miR-181a and its target genes in glioblastoma multiforme (GBM), the expression levels of miR-181a and three target genes in human normal brain tissues and GBM were analyzed in silico using gene microarray, gene ontology, KEGG pathway and hierarchical clustering analysis followed by validation with quantitative RT-PCR. Our results show that miR-181a is down-regulated in GBM patients. The three target genes, ANGPT2, ARHGAP18 and LAMC1, are negatively correlated with the expression of miR-181a. Moreover, high expression of ANGPT2 or LAMC1 together with large size of GBM is correlated with a shorter median overall survival. In conclusion, our results showed that miR-181a and it targets ANGPT2 and LAMC1 might be predictors of prognosis in GBM patients.