Gab2 regulates the migratory behaviors and E-cadherin expression via activation of the PI3K pathway in ovarian cancer cells.
Gab2 regulates the migratory behaviors and E-cadherin expression via activation of the PI3K pathway in ovarian cancer cells.
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DOI：
10.1038/onc.2011.435
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发表时间：
2012-05-17
期刊：
影响因子：
8
通讯作者：
Gu, H.
中科院分区：
文献类型：
--
作者：
Wang, Y.;Sheng, Q.;Spillman, M. A.;Behbakht, K.;Gu, H.
卵巢癌是最致命的妇科恶性肿瘤，通常在癌细胞已经迁移并侵入其他组织和器官时被诊断为晚期和晚期。更好地了解卵巢癌细胞的转移机制对于设计有效的治疗方案至关重要。在这项研究中，我们研究了支架衔接蛋白Gab 2在卵巢癌细胞中的功能。Gab 2被发现在卵巢肿瘤和癌细胞系的子集中过表达。Gab 2的表达主要调节卵巢癌细胞的迁移行为。在Gab 2低表达的卵巢癌细胞中，Gab 2的过表达促进细胞的迁移和侵袭，并下调E-cadherin的表达。相反，在Gab 2高表达的卵巢癌细胞中，Gab 2表达的敲低抑制细胞的迁移和侵袭，并促进E-cadherin的表达。通过表达在PI 3 K和Shp 2-Erk通路的激活中有缺陷的Gab 2野生型和Gab 2突变体，我们发现Gab 2抑制E-钙粘蛋白的表达并增强Zeb 1的表达，Zeb 1是一种参与上皮-间充质转化（EMT）的转录因子，并且通过PI 3 K通路的激活细胞迁移和侵袭。Zeb 1表达的敲低阻断了Gab 2诱导的E-钙粘蛋白表达的抑制和细胞侵袭的增加。PI 3 K的抑制剂LY 294002和GDC-0941或PI 3 K下游靶点mTOR的抑制剂雷帕霉素可以逆转Gab 2对迁移和侵袭的作用。总的来说，我们的研究表明，Gab 2过表达，通过激活PI 3 K-Zeb 1通路，促进卵巢癌细胞EMT的特征。
Ovarian cancer, the most deadly gynecologic malignancy, is often diagnosed late and at the advanced stage when the cancer cells have already migrated and invaded into other tissues and organs. Better understanding of the mechanism of metastasis in ovarian cancer cells is essential to the design of effective therapy. In this study, we investigated the function of scaffolding adaptor protein Gab2 in ovarian cancer cells. Gab2 is found to be overexpressed in a subset of ovarian tumors and cancer cell lines. Gab2 expression mainly regulates the migratory behaviors of ovarian cancer cells. Overexpression of Gab2 promotes the migration and invasion, and down-regulates E-cadherin expression in ovarian cancer cells with low-Gab2 expression. Conversely, knockdown of Gab2 expression inhibits the migration and invasion, and promotes E-cadherin expression in ovarian cancer cells with high-Gab2 expression. By expressing Gab2 wild type and Gab2 mutants that are defective in activation the PI3K and Shp2-Erk pathways, we find that Gab2 inhibits E-cadherin expression and enhances the expression of Zeb1, a transcription factor involved in epithelial-to-mesenchymal transition (EMT), and cell migration and invasion through the activation of the PI3K pathway. Knockdown of Zeb1 expression blocks Gab2-induced suppression of E-cadherin expression and increase in cell invasion. LY294002 and GDC-0941, inhibitors of PI3K, or Rapamycin, an inhibitor of PI3K downstream target mTOR, can reverse the effects of Gab2 on migration and invasion. Overall, our studies reveal that Gab2 overexpression, via activation of the PI3K-Zeb1 pathway, promotes characteristics of EMT in ovarian cancer cells.
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DOI：
10.1038/nrc2644
发表时间：
2009-06
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
通讯作者：
--
DOI：
10.1097/pas.0b013e3181cf3d79
发表时间：
2010-03
期刊：
The American journal of surgical pathology
影响因子：
--
作者：
Kurman RJ;Shih IeM
通讯作者：
Shih IeM
影响因子：
3.3
作者：
Herrera Abreu MT;Hughes WE;Mele K;Lyons RJ;Rickwood D;Browne BC;Bennett HL;Vallotton P;Brummer T;Daly RJ
通讯作者：
Daly RJ
影响因子：
8
作者：
Ke, Y.;Wu, D.;Feng, G-S
通讯作者：
Feng, G-S
影响因子：
6.4
作者：
Fleuren, Emmy D. G.;O'Toole, Sandra;Daly, Roger J.
通讯作者：
Daly, Roger J.