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Rathod , S.S and Rani , S.B. and Khan , M. and Muzumdar , D. and Shiras , A. (2014) Tumor suppressive miRNA-34a suppresses cell proliferation and tumor growth of glioma stem cells by targeting Akt and Wnt signaling pathways. FEBS Open Bio , 4. pp. 485-495.
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8.Dr. Shiras (FEBS Open Bio) Open Access-c@author.pdf - Published Version Download (567Kb) | Preview |
Abstract
MiRNA-34a 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-34a was decreased in a graded manner in glioma and glioma stem cell-lines as compared to normal brain tissues. Ectopic expression of miR-34a in glioma stem cell-lines HNGC- 2 and NSG-K16 decreased the proliferative and migratory potential of these cells, induced cell cycle arrest and caused apoptosis. Notably, the miR-34a 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-34a in glioma stem cells. Rictor, a defining component of mTORC2 complex, is involved in cell survival signaling. mTORC2 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 miR34a over-expression in glioma stem cells profoundly decreased levels of p-AKT (Ser473), increased GSK-3b levels and targeted for degradation b-catenin, an important mediator of Wnt signaling pathway. This led to diminished levels of the Wnt effectors cyclin D1 and c-myc. Collectively, we show that the tumor suppressive function of miR-34a in glioblastoma is mediated via Rictor, which through its effects on AKT/mTOR pathway and Wnt signaling causes pronounced effects on glioma malignancy.
| Item Type: | Article |
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| Additional Information: | This is Open Access Journal (for full text click above weblink) |
| Depositing User: | Mr. Rameshwar Nema |
| Date Deposited: | 06 May 2015 09:08 |
| Last Modified: | 19 Feb 2016 09:57 |
| URI: | http://nccs.sciencecentral.in/id/eprint/170 |
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