Oncogene AEG-1 promotes glioma-induced neurodegeneration by increasing glutamate excitotoxicity.
Oncogene AEG-1 promotes glioma-induced neurodegeneration by increasing glutamate excitotoxicity.
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癌基因 AEG-1 通过增加谷氨酸兴奋毒性来促进神经胶质瘤诱导的神经变性。
DOI：
10.1158/0008-5472.can-11-0782
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发表时间：
2011-10-15
期刊：
影响因子：
11.2
通讯作者：
Fisher PB
中科院分区：
文献类型：
--
作者：
Lee SG;Kim K;Kegelman TP;Dash R;Das SK;Choi JK;Emdad L;Howlett EL;Jeon HY;Su ZZ;Yoo BK;Sarkar D;Kim SH;Kang DC;Fisher PB
恶性胶质瘤的特征是肿瘤的侵袭性生长、弥漫性组织浸润和神经退行性变。虽然谷氨酸兴奋性毒性被认为在胶质瘤诱导的神经退行性变中起关键作用，但控制该过程的机制知之甚少。AEG-1是一种在多种人类癌症中过度表达的癌基因，包括>90%的脑肿瘤。AEG-1还促进胶质瘤的发生，特别是在肿瘤生长和侵袭的背景下，这是胶质瘤的两个主要特征。在本研究中，我们研究了AEG-1对胶质瘤诱导的神经退行性变的贡献。在正常脑组织和胶质瘤患者样本中的Pearson相关系数分析表明AEG-1和星形胶质细胞EAAT 2的主要谷氨酸转运蛋白的表达之间存在强负相关。在正常原代人胎儿星形胶质细胞和T98 G多形性胶质母细胞瘤细胞中进行的功能获得和丧失研究表明，AEG-1通过诱导YY 1活性抑制CBP作为EAAT 2启动子上的共激活物的功能，从而在转录水平上抑制EAAT 2的表达。此外，AEG-1介导的EAAT 2抑制引起神经胶质细胞的谷氨酸摄取减少，导致诱导神经元细胞死亡。这些发现也在神经胶质瘤患者样品中得到证实，表明AEG-1表达与NeuN表达负相关。总之，我们的研究结果表明，AEG-1有助于神经胶质瘤诱导的神经变性，这种致命的肿瘤的标志，通过调节EAAT 2的表达。
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.