Tumor suppressive miRNA-34a suppresses cell proliferation and tumor growth of glioma stem cells by targeting Akt and Wnt signaling pathways.

[severe combined immunodeficiency]

MiRNA-34 a is considered as a potential prognostic marker for glioma , as studies suggest that its expression negatively correlates with patient survival in grade III and IV glial tumors . Here , we show that expression of miR-34 a was decreased in a graded manner in glioma and glioma stem cell-lines as compared to normal brain tissues . Ectopic expression of miR-34 a in glioma stem cell-lines HNGC-2 and NSG-K 16 decreased the proliferative and migratory potential of these cells , induced cell cycle arrest and caused apoptosis . Notably , the miR-34 a glioma cells formed significantly smaller xenografts in immuno-deficient mice as compared with control glioma stem cell-lines . Here , using a bioinformatics approach and various biological assays , we identify Rictor , as a novel target for miR-34 a in glioma stem cells . Rictor , a defining component of mTORC 2 complex , is involved in cell survival signaling . mTORC 2 lays downstream of Akt , and thus is a direct activator of Akt . Our earlier studies have elaborated on role of Rictor in glioma invasion (Das et al ., 2011 ). Here , we demonstrate that miR 34 a over-expression in glioma stem cells profoundly decreased levels of p -AKT (Ser 473 ), increased GSK -3 β levels and targeted for degradation β-catenin , an important mediator of Wnt signaling pathway . This led to diminished levels of the Wnt effectors cyclin D 1 and c-myc . Collectively , we show that the tumor suppressive function of miR-34 a in glioblastoma is mediated via Rictor , which through its effects on AKT /mTOR pathway and Wnt signaling causes pronounced effects on glioma malignancy .

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severe combined immunodeficiency

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