Astrocyte Elevated Gene-1 Regulates {beta}-Catenin Signaling to Maintain Glioma Stem-like Stemness and Self-Renewal

Glioblastoma multiforme is a common malignant brain tumor that portends extremely poor patient survival. Recent studies reveal that glioma stem-like cells (GSC) are responsible for glioblastoma multiforme escape from chemo-radiotherapy and mediators of tumor relapse. Previous studies suggest that AEG-1 (MTDH), an oncogene upregulated in most types of cancers, including glioblastoma multiforme, plays a focal role linking multiple signaling pathways in tumorigenesis. We now report a crucial role of AEG-1 in glioma stem cell biology. Primary glioblastoma multiforme cells were isolated from tumor specimens and cultured as neurospheres. Using the surface marker CD133, negative and positive cells were separated as nonstem and stem populations by cell sorting. Tissue samples and low passage cells were characterized and compared with normal controls. Functional biological assays were performed to measure stemness, self-renewal, differentiation, adhesion, protein–protein interactions, and cell signaling. AEG-1 was upregulated in all glioblastoma multiforme neurospheres compared with normal neural stem cells. Expression of AEG-1 was strongly associated with stem cell markers CD133 and SOX2. AEG-1 facilitated β-catenin translocation into the nucleus by forming a complex with LEF1 and β-catenin, subsequently activating Wnt signaling downstream genes. Through an AEG-1/Akt/GSK3β signaling axis, AEG-1 controlled phosphorylation levels of β-catenin that stabilized the protein.

Implications: This study discovers a previously unrecognized role of AEG-1 in GSC biology and supports the significance of this gene as a potential therapeutic target for glioblastoma multiforme. Mol Cancer Res; 15(2); 225–33. ©2016 AACR.

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