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J Cell Mol Med. 2017 Dec;21(12):3481-3493. doi: 10.1111/jcmm.13258. Epub 2017 Jun 29.

AEG-1 induces gastric cancer metastasis by upregulation of eIF4E expression.

Author information

1
Department of Pharmacology, Nanjing Medical University, Nanjing, Jiangsu, China.
2
Department of General Surgery, Medical Oncology and Pathology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu, China.
3
Department of Basic Medicine, Kangda College of Nanjing Medical University, Lianyungang, Jiangsu, China.
4
Department of Pathology, Nanjing Medical University Affiliated Nanjing Hospital (Nanjing First Hospital), Nanjing, Jiangsu, China.

Abstract

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.

KEYWORDS:

AEG-1; eIF4E; epithelial-mesenchymal transition; gastric cancer; metastasis

PMID:
28661037
PMCID:
PMC5706588
DOI:
10.1111/jcmm.13258
[Indexed for MEDLINE]
Free PMC Article

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