Wip1 suppresses ovarian cancer metastasis through the ATM/AKT/Snail mediated signaling
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Sheng Yin1,2,3,*, Pan Wang1,2,*, Lina Yang4,5, Yang Liu2, Yan Wang2, Mingming Liu2, Zihao Qi2, Jiao Meng2, Ting-Yan Shi3, Gong Yang2,4,5, Rongyu Zang3
1Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China
2Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China
3Ovarian Cancer Program, Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Zhongshan Hospital, Fudan University, Shanghai 200032, China
4Department of Gynecology and Obstetrics, The Fifth People’s Hospital of Shanghai Fudan University, Shanghai 200240, China
5Central Laboratory, The Fifth People's Hospital of Shanghai Fudan University, Shanghai 200240, China
*These authors contributed equally to this work
Rongyu Zang, email: [email protected]
Gong Yang, email: [email protected]
Keywords: Wip1, metastasis, ovarian cancer, EMT
Received: December 05, 2015 Accepted: March 28, 2016 Published: April 18, 2016
Inactivation of p53 greatly contributes to serous ovarian cancer, while the role of the wild-type p53 induced phosphatase 1 (Wip1) is quite unclear. In this study, by silencing or overexpression of Wip1, we found that Wip1 suppressed ovarian cancer cell invasion, migration, epithelial to mesenchymal transition (EMT), and ovarian cancer metastasis in xenograft animal models. Mechanistic studies showed that Wip1 may block ovarian cancer metastasis through inhibition of Snail and p-Akt expression because silencing or overexpression of Wip1 either upregulated or downregulated the expression of Snail and p-Akt (Ser 473), while further knockdown of Snail by shRNA or inhibition of p-Akt by a chemical compound attenuated cell invasion, migration and EMT in Wip1 silencing cells. We also found that the phosphorylation of Akt at Ser 473 might be mediated through p-ATM (Ser 1981). Thus, Wip1 may suppress ovarian cancer metastasis through negative regulation of p-ATM, p-Akt, and Snail, which was also evidenced in the limited clinical specimens. Therefore, our data may provide a novel therapeutic indication for serous ovarian cancer based on the uncovered mechanism associated with the precise function of Wip1 independent of p53.
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