Wip1 suppresses ovarian cancer metastasis through the ATM/AKT/Snail mediated signaling.
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.
Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China.|Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China.|Ovarian Cancer Program, Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Sheng
S
Yin
Department of Gynecological Oncology, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China.|Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Pan
P
Wang
Department of Gynecology and Obstetrics, The Fifth People's Hospital of Shanghai Fudan University, Shanghai 200240, China.|Central Laboratory, The Fifth People's Hospital of Shanghai Fudan University, Shanghai 200240, China.
Lina
L
Yang
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Yang
Y
Liu
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Yan
Y
Wang
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Mingming
M
Liu
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Zihao
Z
Qi
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China.
Jiao
J
Meng
Ovarian Cancer Program, Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Ting-Yan
TY
Shi
Cancer Institute, Fudan University Shanghai Cancer Center, Shanghai Medical College, Fudan University, Shanghai 200032, China.|Department of Gynecology and Obstetrics, The Fifth People's Hospital of Shanghai Fudan University, Shanghai 200240, China.|Central Laboratory, The Fifth People's Hospital of Shanghai Fudan University, Shanghai 200240, China.
Gong
G
Yang
Ovarian Cancer Program, Division of Gynecologic Oncology, Department of Gynecology and Obstetrics, Zhongshan Hospital, Fudan University, Shanghai 200032, China.
Rongyu
R
Zang
D000818:Animals; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology; D005260:Female; D064593:Heterografts; D006801:Humans; D051379:Mice; D009361:Neoplasm Invasiveness / Q000473:pathology; D009375:Neoplasms, Glandular and Epithelial / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000378:metabolism / Q000473:pathology*; D000071636:Protein Phosphatase 2C / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology; D000071250:Snail Family Transcription Factors / Q000378:metabolism*
D000071250:Snail Family Transcription Factors; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D051057:Proto-Oncogene Proteins c-akt; C000607458:PPM1D protein, human; D000071636:Protein Phosphatase 2C
EMT; Wip1; metastasis; ovarian cancer