Tumor suppressive miRNA-34a suppresses cell proliferation and tumor growth of glioma stem cells by targeting Akt and Wnt signaling pathways
| العنوان: | Tumor suppressive miRNA-34a suppresses cell proliferation and tumor growth of glioma stem cells by targeting Akt and Wnt signaling pathways |
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| المؤلفون: | Sachin Shivaji Rathod, Dattatraya Muzumdar, Sandhya B. Rani, Mohsina Khan, Anjali Shiras |
| المصدر: | FEBS Open Bio, Vol 4, Iss C, Pp 485-495 (2014) FEBS Open Bio |
| بيانات النشر: | Wiley, 2014. |
| سنة النشر: | 2014 |
| مصطلحات موضوعية: | Beta-catenin, Mesenchymal, qRT-PCR, quantitative real time PCR, GSC, glioma stem cell, PARP, poly ADP-ribose polymerases, CNS, central nervous system, mTORC2, Article, General Biochemistry, Genetics and Molecular Biology, Rictor, bFGF, basic fibroblast growth factor, Glioma, medicine, Epithelial–mesenchymal transition, neoplasms, Protein kinase B, lcsh:QH301-705.5, GSK-3β, glycogen synthase kinase 3β, TCGA, the cancer genome atlas database, PI3K/AKT/mTOR pathway, EGF, epidermal growth factor, EV, empty vector, NOD/SCID, nonobese diabetic/severe combined immunodeficiency, biology, PDGFRA, platelet-derived growth factor receptor-α, Wnt signaling pathway, GBM, glioblastoma multiforme, medicine.disease, nervous system diseases, GIC, glioma initiating cell, lcsh:Biology (General), biology.protein, Cancer research, Stem cell, Heterogeneity, Glioblastoma, EMT, epithelial–mesenchymal transition |
| الوصف: | Highlights • miR-34a was decreased in both glioma and glioma stem cell-lines as compared to normal brain tissues. • Glioma stem cell-lines HNGC-2 and NSG-K16 possess the mesenchymal glioblastoma phenotype. • miR-34a over-expression in these cell lines decreased their proliferative and migratory potential, and induced apoptosis. • Rictor, a part of the mTORC2 complex, is a novel target for miR-34a in glioma stem cells. • The tumor suppressive function of miR-34a is mediated via Rictor and affects the AKT/mTOR pathway and Wnt signaling. 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-3β levels and targeted for degradation β-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. |
| اللغة: | English |
| تدمد: | 2211-5463 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::d57f3444d53734329ba31047c9edb191Test http://www.sciencedirect.com/science/article/pii/S2211546314000503Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....d57f3444d53734329ba31047c9edb191 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22115463 |
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