Aggressive tumor growth, diffuse tissue invasion and neurodegeneration are hallmarks of malignant glioma. Although glutamate excitotoxicity is considered to play a key role in glioma-induced neurodegeneration, the mechanism(s) controlling this process is poorly understood. AEG-1 is an oncogene overexpressed in multiple types of human cancers including >90% of brain tumors. AEG-1 also promotes gliomagenesis particularly in the context of tumor growth and invasion, two primary characteristics of glioma. In the present study, we investigated the contribution of AEG-1 to glioma-induced neurodegeneration. Pearson correlation coefficient analysis in normal brain tissues and glioma patient samples indicated a strong negative correlation between expression of AEG-1 and a primary glutamate transporter of astrocytes EAAT2. Gain and loss of function studies in normal primary human fetal astrocytes and T98G glioblastoma multiforme cells revealed that AEG-1 repressed EAAT2 expression at a transcriptional level by inducing YY1 activity to inhibit CBP function as a coactivator on the EAAT2 promoter. In addition, AEG-1-mediated EAAT2 repression caused a reduction of glutamate uptake by glial cells, resulting in induction of neuronal cell death. These findings were also confirmed in glioma patient samples demonstrating that AEG-1 expression negatively correlated with NeuN expression. Taken together, our findings suggest that AEG-1 contributes to glioma-induced neurodegeneration, a hallmark of this fatal tumor, through regulation of EAAT2 expression.

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Recently, many studies have shown that granulocyte macrophage-colony stimulating factor (GM-CSF) has anti-apoptotic activity and regulates the expression of anti-apoptotic genes including Bcl-2 family proteins in neuronal cells in vitro and in vivo. This study investigated detailed mechanism of GM-CSF involved in its anti-apoptotic activity and regulation of Bcl-2 expression in neural progenitor cells (NPCs) as a model. NPCs were cultured from the brain of E13 ICR mouse. When NPCs were treated with staurosporine at 1 μM, apoptosis occurred in more than 30% of cells in TUNEL assay. However, apoptosis was significantly inhibited by pre-treatment with GM-CSF at 10 ng/ml. Under the same experimental condition, the expression of both Bcl-2 and Bcl-xl was clearly induced by GM-CSF regardless of staurosporine treatment in RT-PCR and Western blot analyses. GM-CSF was shown to induce the expression of Bcl-2 and Bcl-xl via Janus tyrosine kinase (JAK) but not via phosphatidylinositol 3-kinase (PI3K) or RAS-mitogen activated protein kinase kinase-1 (MEK-1) using specific signal pathway inhibitors. Further analyses showed that the expression of Bcl-2 and Bcl-xl was induced by GM-CSF via signal transducers and activators of transcription 5 (STAT5) and STAT3, respectively. In addition, JAK/STAT5-Bcl-2 pathway but not JAK/STAT3-Bcl-xl pathway was responsible for the anti-apoptotic activity of GM-CSF in NPCs in TUNEL assay. To our knowledge, this study is the first report that shows differential roles of Bcl-2 and Bcl-xl, and their regulation mechanism involved in the anti-apoptotic activity of GM-CSF in NPCs.

GM-CSF plays a role in the nervous system, particularly in cases of injury. A therapeutic effect of GM-CSF has been reported in rat models of various central nervous system injuries. We previously showed that GM-CSF could enhance long-term recovery in a rat spinal cord injury model, inhibiting glial scar formation and increasing the integrity of axonal structure. Here, we investigated molecular the mechanism(s) by which GM-CSF suppressed glial scar formation in an in vitro system using primary astrocytes treated with TGF-β. GM-CSF repressed the expression of chondroitin sulfate proteoglycan (CSPG) core proteins in astrocytes treated with TGF-β. GM-CSF also inhibited the TGF-β-induced Rho-ROCK pathway, which is important in CSPG expression. Finally, the inhibitory effect of GM-CSF was blocked by a JAK inhibitor. These results may provide the basis for GM-CSF’s effects in glial scar inhibition and ultimately for its therapeutic effect on neural cell injuries. [BMB Reports 2014; 47(12): 679-684]

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