RASAL2 down-regulation in ovarian cancer promotes epithelial-mesenchymal transition and metastasis
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Yuting Huang1,2,*, Meng Zhao2,*, Haixu Xu2, Ke Wang1, Zheng Fu2, Yuan Jiang2 and Zhi Yao2
1 Tianjin Medical University Cancer Institute and Hospital, National Clinical Research Center of Cancer, Key Laboratory of Cancer Prevention and Therapy, Tianjin, P.R. China
2 Department of Immunology, Tianjin Key Laboratory of Cellular and Molecular Immunology, Key Laboratory of Educational Ministry of China, School of Basic Medical Sciences, Tianjin Medical University, Tianjin, P.R. China
* These authors contributed equally to this work
Zhi Yao, email:
Keywords: ovarian cancer, RASAL2, EMT, MAPK, metastasis
Received: May 28, 2014 Accepted: July 22, 2014 Published: July 23, 2014
Ovarian cancer is the most lethal gynecologic malignancy, and transcoelomic metastasis is responsible for the greatest disease mortality. Although intensive efforts have been made, the mechanism behind this process remains unclear. RASAL2 is a GTPase activating proteins (GAPs) which was recently reported as a tumor suppressor in breast cancer. In this study, we identified RASAL2 as a regulator of epithelial-mesenchymal transition (EMT) and metastasis in ovarian cancer. RASAL2 was down-regulated in ovarian cancer samples compared with normal tissue samples, especially in advanced stages and grades. RASAL2 knockdown in ovarian cancer cell lines promoted in vitro anchorage-independent growth, cell migration and invasion and in vivo tumor formation. Moreover, we observed EMT in RASAL2-depleted cells. E-cadherin-mediated cell-cell adhesion was attenuated, and mesenchymal markers were up-regulated. Further investigation revealed that the oncogenic role of RASAL2 down-regulation was mediated by the Ras-ERK pathway. RASAL2 knockdown activated the Ras-ERK pathway, and inhibition of the pathway reversed the functional effects of RASAL2 depletion. Together, our results implicate RASAL2 as an EMT regulator and tumor suppressor in ovarian cancer, and down-regulation of RASAL2 promotes ovarian cancer progression.
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