AEG-1 induces gastric cancer metastasis by upregulation of eIF4E expression.
AEG-1 induces gastric cancer metastasis by upregulation of eIF4E expression.
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AEG-1通过上调eIF4E表达诱导胃癌转移。
DOI：
10.1111/jcmm.13258
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发表时间：
2017-12
影响因子：
5.3
通讯作者：
Wang X
中科院分区：
文献类型：
--
作者：
Wu S;Yang L;Wu D;Gao Z;Li P;Huang W;Wang X
胃癌是全球第三大癌症相关死亡原因，有淋巴结、腹膜和远处转移的患者预后较差。星形胶质细胞上调基因-1(AEG-1)的过度表达与胃癌的进展和转移密切相关。然而，它的机制还很不清楚。在这项研究中，我们发现AEG-1的高表达与人胃癌组织中的转移有关。此外，AEG-1的功能增强或功能丧失分别促进或抑制了胃癌细胞上皮-间充质转化(EMT)、迁移和侵袭。AEG-1正向调节eIF4E、MMP9和Twist的表达。通过转染过表达载体或siRNAs来操纵eIF4E的表达，可部分消除AEG-1调控的EMT、细胞迁移和侵袭。此外，eIF4E的过表达或下调促进或抑制了EMT、细胞的迁移和侵袭，同时上调了MMP9和Twist的表达，而操纵eIF4E的表达部分地抑制了AEG-1诱导的MMP9和Twist的表达。最后，沉默AEG-1的表达不仅抑制了裸鼠移植瘤模型中eIF4E、MMP9和Twist的表达，同时抑制了肿瘤的生长，而且还抑制了裸鼠原位移植瘤的淋巴和腹膜转移。提示AEG-1通过上调eIF4E介导的基质金属蛋白酶-9和Twist的表达促进胃癌转移，为肿瘤转移提供了新的诊断标记物和治疗靶点。
Gastric cancer is the third leading cause of cancer‐related deaths worldwide, and patients with lymph node, peritoneal and distant metastasis have a poor prognosis. Overexpression of Astrocyte‐elevated gene‐1 (AEG‐1) has been reported to be correlated with the progression and metastasis of gastric cancer. However, its mechanisms are quite unclear. In this study, we found that elevated expression of AEG‐1 was correlated with metastasis in human gastric cancer tissues. Moreover, gain‐ or loss‐of‐function of AEG‐1, respectively, promoted or suppressed epithelial–mesenchymal transition (EMT), migration and invasion of gastric cancer cells. AEG‐1 positively regulated eIF4E, MMP‐9 and Twist expression. Manipulating eIF4E expression by transfection of overexpression constructs or siRNAs partially eliminated AEG‐1‐regulated EMT, cell migration and invasion. In addition, overexpression or knockdown of eIF4E promoted or suppressed EMT, cell migration and invasion in parallel with upregulation of MMP‐9 and Twist expression, while manipulating eIF4E expression partially abrogated AEG‐1‐induced MMP‐9 and Twist. Finally, silencing of AEG‐1 expression not only inhibited tumour growth in parallel with downregulation of eIF4E, MMP‐9 and Twist expression in a xenograft nude mouse model, but also suppressed lymph node and peritoneal metastasis of gastric cancer in an orthotopic nude mouse model. These findings suggest that AEG‐1 promotes gastric cancer metastasis through upregulation of eIF4E‐mediated MMP‐9 and Twist, which provides new diagnostic markers and therapeutic targets for cancer metastasis.
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