Astrocyte elevated gene-1 (AEG-1) functions as an oncogene and regulates angiogenesis
Astrocyte elevated gene-1 (AEG-1) functions as an oncogene and regulates angiogenesis
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DOI：
10.1073/pnas.0910936106
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发表时间：
2009-12-15
影响因子：
11.1
通讯作者：
Fisher, Paul B.
中科院分区：
文献类型：
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作者：
Emdad, Luni;Lee, Seok-Geun;Fisher, Paul B.
星形胶质细胞升高的基因-1（AEG-1）表达在多种癌症中增加，并通过磷脂酰肌醇3-激酶（PI 3 K）/Akt信号通路在Ha-ras介导的肿瘤发生中发挥核心作用。此外，AEG-1的过表达通过激活PI 3 K/Akt信号传导保护原代和转化的人和大鼠细胞免于血清饥饿诱导的凋亡。这些发现表明，但不能证明，AEG-1可能作为一个致癌基因。我们现在提供了明确的证据表明，AEG-1确实是一个转化癌基因，并表明AEG-1在正常的永生克隆大鼠胚胎成纤维细胞（CREF）细胞中的稳定表达诱导形态转化，并增强软琼脂中的侵袭和锚定非依赖性生长，这是与细胞转化相关的两个基本生物学事件。此外，表达AEG-1的CREF克隆在裸鼠中形成侵袭性肿瘤。肿瘤切片的免疫组织化学分析表明，AEG-1表达肿瘤在整个肿瘤切片中具有增加的微血管密度。AEG-1的过表达增加了血管生成分子标志物的表达，包括血管生成素-1、基质金属蛋白酶-2和缺氧诱导因子1-α。体外血管生成研究进一步证明AEG-1通过PI 3 K/Akt信号通路促进Matrigel中的管形成并增加人脐静脉内皮细胞的侵袭。由AEG-1诱导的管形成与血管生成标志物（包括Tie 2和缺氧诱导因子-α）的表达增加相关，并且用Tie 2 siRNA阻断AEG-1诱导的Tie 2显著抑制基质胶中AEG-1诱导的管形成。总之，我们的研究结果表明，异常AEG-1表达在调节致癌转化和血管生成中起着主导的积极作用。这些发现表明AEG-1可能为直接抑制癌症表型提供可行的靶点。
Astrocyte-elevated gene-1 (AEG-1) expression is increased in multiple cancers and plays a central role in Ha-ras-mediated oncogenesis through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Additionally, overexpression of AEG-1 protects primary and transformed human and rat cells from serum starvation-induced apoptosis through activation of PI3K/Akt signaling. These findings suggest, but do not prove, that AEG-1 may function as an oncogene. We now provide definitive evidence that AEG-1 is indeed a transforming oncogene and show that stable expression of AEG-1 in normal immortal cloned rat embryo fibroblast (CREF) cells induces morphological transformation and enhances invasion and anchorage-independent growth in soft agar, two fundamental biological events associated with cellular transformation. Additionally, AEG-1-expressing CREF clones form aggressive tumors in nude mice. Immunohistochemistry analysis of tumor sections demonstrates that AEG-1-expressing tumors have increased microvessel density throughout the entire tumor sections. Overexpression of AEG-1 increases expression of molecular markers of angiogenesis, including angiopoietin-1, matrix metalloprotease-2, and hypoxia-inducible factor 1-alpha. In vitro angiogenesis studies further demonstrate that AEG-1 promotes tube formation in Matrigel and increases invasion of human umbilical vein endothelial cells via the PI3K/Akt signaling pathway. Tube formation induced by AEG-1 correlates with increased expression of angiogenesis markers, including Tie2 and hypoxia-inducible factor-alpha, and blocking AEG-1-induced Tie2 with Tie2 siRNA significantly inhibits AEG-1-induced tube formation in Matrigel. Overall, our findings demonstrate that aberrant AEG-1 expression plays a dominant positive role in regulating oncogenic transformation and angiogenesis. These findings suggest that AEG-1 may provide a viable target for directly suppressing the cancer phenotype.