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Wip1通过ATM/AKT/蜗牛介导的信号传导抑制卵巢癌转移。

Wip1 suppresses ovarian cancer metastasis through the ATM/AKT/Snail mediated signaling.

作者信息

Yin Sheng, Wang Pan, Yang Lina, Liu Yang, Wang Yan, Liu Mingming, Qi Zihao, Meng Jiao, Shi Ting-Yan, Yang Gong, Zang Rongyu

机构信息

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.

出版信息

Oncotarget. 2016 May 17;7(20):29359-70. doi: 10.18632/oncotarget.8833.

DOI:10.18632/oncotarget.8833
PMID:27121065
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5045401/
Abstract

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.

摘要

p53失活在浆液性卵巢癌中起很大作用，而野生型p53诱导磷酸酶1（Wip1）的作用尚不清楚。在本研究中，通过沉默或过表达Wip1，我们发现Wip1在异种移植动物模型中抑制卵巢癌细胞侵袭、迁移、上皮-间质转化（EMT）以及卵巢癌转移。机制研究表明，Wip1可能通过抑制Snail和p-Akt表达来阻断卵巢癌转移，因为沉默或过表达Wip1会分别上调或下调Snail和p-Akt（Ser 473）的表达，而通过shRNA进一步敲低Snail或用化合物抑制p-Akt可减弱Wip1沉默细胞中的细胞侵袭、迁移和EMT。我们还发现，Akt在Ser 473位点的磷酸化可能是通过p-ATM（Ser 1981）介导的。因此，Wip1可能通过对p-ATM、p-Akt和Snail的负调控来抑制卵巢癌转移，这在有限的临床标本中也得到了证实。因此，我们的数据可能基于与Wip1独立于p53的确切功能相关的未揭示机制，为浆液性卵巢癌提供一种新的治疗靶点。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/04e3f76e1c24/oncotarget-07-29359-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/6d4cf470a326/oncotarget-07-29359-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/375c4ae6a3f4/oncotarget-07-29359-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/03abbdafbba3/oncotarget-07-29359-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/4ca815e5c42a/oncotarget-07-29359-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/3513412a6574/oncotarget-07-29359-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/2beb5d5c6ac8/oncotarget-07-29359-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/f626fab9709b/oncotarget-07-29359-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/04e3f76e1c24/oncotarget-07-29359-g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/6d4cf470a326/oncotarget-07-29359-g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/375c4ae6a3f4/oncotarget-07-29359-g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/03abbdafbba3/oncotarget-07-29359-g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/4ca815e5c42a/oncotarget-07-29359-g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/3513412a6574/oncotarget-07-29359-g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/2beb5d5c6ac8/oncotarget-07-29359-g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/f626fab9709b/oncotarget-07-29359-g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d2cd/5045401/04e3f76e1c24/oncotarget-07-29359-g008.jpg

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