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

作者：Hu Bin; Emdad Luni; Kegelman Timothy P; Shen Xue Ning; Das Swadesh K; Sarkar Devanand; Fisher Paul B

来源：Molecular Cancer Research, 2017, 15(2): 225-233.

DOI：10.1158/1541-7786.MCR-16-0239

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 mea-sure 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 beta-catenin translocation into the nucleus by forming a complex with LEF1 and beta-catenin, subsequently activating Wnt signaling downstream genes. Through an AEG-1/Akt/GSK3 beta signaling axis, AEG-1 controlled phosphorylation levels of beta-catenin that stabilized the protein.

• 出版日期2017-2