來自弗吉尼亞聯(lián)邦大學(xué)Massey癌癥中心和VCU分子醫(yī)學(xué)研究所的研究人員發(fā)現(xiàn)了多形性膠質(zhì)母細(xì)胞瘤（GBM）促進(jìn)神經(jīng)元功能喪失或死亡也就是神經(jīng)退行性變的一種機(jī)制,，GBM是最常見的腦腫瘤。這一發(fā)現(xiàn)可能促使抑制GBM神經(jīng)退行性變的新治療方法應(yīng)運(yùn)而生,，也可能用于其他神經(jīng)退行性疾病,。
這項(xiàng)研究最近發(fā)表在《癌癥研究》雜志上,，由Thelma Newmeyer Corman腫瘤研究主席Paul B.Fisher，M.博士主持,。Fisher博士同時(shí)也是VCU Massey癌癥分子遺傳學(xué)項(xiàng)目的合作領(lǐng)導(dǎo)者,，VCU醫(yī)學(xué)院人類和分子遺傳學(xué)系教授主席、VCU分子醫(yī)學(xué)研究所主任,。研究者發(fā)現(xiàn),，癌基因（導(dǎo)致癌癥發(fā)生的基因）星形膠質(zhì)細(xì)胞上調(diào)基因（AEG）-1通過增加谷氨酸的神經(jīng)元毒性促進(jìn)神經(jīng)退行性變。谷氨酸在神經(jīng)元之間的信號傳輸中發(fā)揮重要作用,，對于學(xué)習(xí)和記憶也很重要,。另一方面，谷氨酸可以在突觸或神經(jīng)元之間的間隙中聚集,，通過過度刺激導(dǎo)致神經(jīng)元死亡,，也就是我們所知的興奮毒性。
這項(xiàng)研究首次為GBM,、神經(jīng)退行性變和谷氨酸轉(zhuǎn)運(yùn)提供了直接機(jī)制,，解釋了GBM通過表達(dá)AEG-1癌基因引起神經(jīng)元死亡的過程。AEG–1最初是由Fisher實(shí)驗(yàn)室克隆的,，90%的腦腫瘤過表達(dá)AEG-1,。
“膠質(zhì)瘤是最常見的腦腫瘤，是20至39歲成年人癌癥死亡的第二大原因,，”Fisher說,。“在強(qiáng)調(diào)AEG-1在腦腫瘤發(fā)生、發(fā)展和神經(jīng)退行性疾病的重要性時(shí),，我們已經(jīng)確定了通過干預(yù)治療抑制上述過程的新靶點(diǎn),。”
Fisher的團(tuán)隊(duì)證實(shí)，AEG-1與興奮性氨基酸轉(zhuǎn)運(yùn)體2（EEAT2）的表達(dá)呈負(fù)相關(guān),，EEAT2是大腦和脊髓膠質(zhì)細(xì)胞（環(huán)繞神經(jīng)元細(xì)胞,，提供支持和隔離）主要的谷氨酸轉(zhuǎn)運(yùn)體。EEAT2對于保持突觸部位適當(dāng)?shù)墓劝彼崴绞潜夭豢缮俚模瑹o法調(diào)節(jié)谷氨酸水平將導(dǎo)致興奮毒性,。研究人員還發(fā)現(xiàn),，AEG-1抑制EEAT2的轉(zhuǎn)錄表達(dá)，也就是基因在細(xì)胞核中表達(dá)的過程,，通過多種機(jī)制導(dǎo)致谷氨酸過量引起興奮毒性,。使用GBM患者樣本，也證實(shí)了AEG-1的表達(dá)和神經(jīng)毒性之間的這種關(guān)系,。
“了解谷氨酸轉(zhuǎn)運(yùn)對于多種神經(jīng)系統(tǒng)退行性疾病,，包括腦膠質(zhì)瘤誘導(dǎo)的神經(jīng)退行性疾病、肌萎縮性側(cè)索硬化癥（ALS）,、亨廷頓氏病,、阿爾茨海默氏癥、癲癇,、腦缺血具有非常重要的意義,，”Fisher說。“我們的實(shí)驗(yàn)室第一個(gè)克隆了EEAT2子,，我們計(jì)劃用它來篩選能夠調(diào)節(jié)細(xì)胞外谷氨酸轉(zhuǎn)運(yùn)并防止神經(jīng)退行性變的小分子或藥物,。”
下一步，F(xiàn)isher和他的團(tuán)隊(duì)將努力構(gòu)建先進(jìn)的動物模型,，進(jìn)一步研究AEG-1的作用和谷氨酸在大腦發(fā)育中的作用和功能,。一旦建立成功，這些模型也將有助于測試小分子篩選過程中所確定的藥物,。最終目標(biāo)是利用本研究開發(fā)出治療GBM和其他疾病所致神經(jīng)退行性變的方法,。
Fisher研究的合作作者：VCU Massey癌癥中心VCU醫(yī)學(xué)院人類和分子遺傳學(xué)系VSU分子醫(yī)學(xué)研究所Keetae Kim博士，Timothy P.Kegelman碩士,，博士在讀,，Rupesh Dash博士，Swadesh K. Das博士,，Luni Emdad,，MBBS博士，EricL.Howlett博士,，ZhaoZhong Su博士和Devanand Sarkar,，MBBS博士。韓國漢城東方醫(yī)學(xué)學(xué)院癌癥預(yù)防材料開發(fā)研究中心李錫根博士,，韓國江原道春川Hallym大學(xué)Ilsong生命科學(xué)研究所Dong-chul Kang博士,。(生物谷Bioon.com)
doi:10.1158/0008-5472.CAN-11-0782
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PMID:
Oncogene AEG-1 Promotes Glioma-Induced Neurodegeneration by Increasing Glutamate Excitotoxicity
Seok-Geun Lee, Keetae Kim, Timothy P. Kegelman, Rupesh Dash, Swadesh K. Das, Jung Kyoung Choi, Luni Emdad, Eric L. Howlett, Hyun Yong Jeon, Zhao Zhong Su, Byoung Kwon Yoo, Devanand Sarkar, Sung-Hoon Kim, Dong-Chul Kang, and Paul B. Fisher
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. Astrocyte elevated gene-1 (AEG-1) is an oncogene that is overexpressed in several types of human cancers, including more than 90% of brain tumors. In addition, AEG-1 promotes gliomagenesis, particularly in the context of tumor growth and invasion, 2 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 samples from glioma patients 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 samples from glioma patients showing 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.
