Astrocyte Elevated Gene-1 Upregulates Matrix Metalloproteinase-9 and Induces Human Glioma Invasion
Astrocyte Elevated Gene-1 Upregulates Matrix Metalloproteinase-9 and Induces Human Glioma Invasion
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星形胶质细胞基因 1 升高上调基质金属蛋白酶 9 并诱导人胶质瘤侵袭
DOI：
10.1158/0008-5472.can-09-3838
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发表时间：
2010-05-01
期刊：
影响因子：
11.2
通讯作者：
Li, Mengfeng
中科院分区：
文献类型：
--
作者：
Liu, Liping;Wu, Jueheng;Li, Mengfeng
恶性胶质瘤的预后差主要归因于其高度侵袭性。然而，胶质瘤细胞侵袭性的分子机制仍有待阐明。本研究发现，星形胶质细胞升高基因-1（AEG-1）在人脑胶质瘤细胞系和胶质瘤组织中的表达均高于正常星形胶质细胞和脑组织。AEG-1在296例胶质瘤切片中有265例（89.5%）表达上调，且AEG-1表达水平与胶质瘤的临床病理分期显著相关。AEG-1的异位表达或短发夹RNA沉默分别显著增强或抑制胶质瘤细胞的侵袭能力。在分子水平上，我们发现在胶质瘤细胞中上调的AEG-1与基质金属蛋白酶-9（MMP-9）启动子相互作用，反式激活MMP-9的表达，而AEG-1表达的敲低降低了MMP-9的水平。MMP-9启动子区有两个区域参与与AEG-1的相互作用。内源性MMP-9的抑制废除AEG-1的侵袭力的影响。与这些观察结果一致，免疫染色分析揭示了AEG-1和MMP-9在一组临床胶质瘤样本中的表达之间的显著相关性。此外，颅内异种移植的胶质瘤细胞工程表达AEG-1是高度侵袭性的亲本细胞相比，表达高水平的MMP-9。总的来说，这些发现提供了证据表明AEG-1通过增强MMP-9转录和肿瘤细胞侵袭性促进胶质瘤进展，并强调了AEG-1在胶质瘤发展和进展中的重要性。Cancer Res; 70（9）; 3750-9. (C)2010年AACR。
The poor prognosis of malignant gliomas is largely attributed to their highly invasive nature. The molecular mechanism underlying the invasiveness of glioma cells, however, remains to be elucidated. The present study found that astrocyte elevated gene-1 (AEG-1) was upregulated in human glioma cell lines and glioma tissues compared with normal astrocytes and brain tissues. AEG-1 was found to be upregulated in 265 of 296 (89.5%) glioma sections, and the AEG-1 expression level significantly correlated with clinicopathologic stages of gliomas. Ectopic expression or short hairpin RNA silencing of AEG-1 significantly enhanced or inhibited, respectively, the invasive ability of glioma cells. At the molecular level, we showed that upregulated AEG-1 in glioma cells interacted with matrix metalloproteinase-9 (MMP-9) promoter and transactivated MMP-9 expression, whereas knockdown of AEG-1 expression reduced the level of MMP-9. Two regions in MMP-9 promoter were found to be involved in the interaction with AEG-1. Suppression of endogenous MMP-9 abrogated the effects of AEG-1 on invasiveness. Consistent with these observations, immunostaining analysis revealed a significant correlation between the expressions of AEG-1 and MMP-9 in a cohort of clinical glioma samples. Moreover, intracranial xenografts of glioma cells engineered to express AEG-1 were highly invasive compared with the parental cells and expressed high level of MMP-9. Collectively, these findings provide evidence that AEG-1 contributes to glioma progression by enhancing MMP-9 transcription and, hence, tumor cell invasiveness, and underscore the importance of AEG-1 in glioma development and progression. Cancer Res; 70(9); 3750-9. (C) 2010 AACR.