EphB3 Stimulates Cell Migration and Metastasis in a Kinase-dependent Manner through Vav2-Rho GTPase Axis in Papillary Thyroid Cancer
EphB3 Stimulates Cell Migration and Metastasis in a Kinase-dependent Manner through Vav2-Rho GTPase Axis in Papillary Thyroid Cancer
复制标题
EphB3 通过 Vav2-Rho GTPase 轴以激酶依赖性方式刺激甲状腺乳头状癌中的细胞迁移和转移
DOI：
10.1074/jbc.m116.750349
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发表时间：
2017-01-20
影响因子：
4.8
通讯作者：
Xie, Dong
中科院分区：
文献类型：
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作者：
Li, Jing-Jing;Sun, Zhi-Jian;Xie, Dong
Eph受体是跨膜酪氨酸激酶受体中最大的一个亚家族，它越来越多地参与各种生理和病理过程，近年来Eph家族成员在肿瘤发生中的作用越来越受到关注。在本研究中，我们探讨了Eph家族成员EphB3在甲状腺乳头状癌（PTC）中的作用。我们发现EphB3在PTC中的表达明显升高。EphB3过表达或EfnB1-Fc/ EfnB1-Fc激活EphB3均可刺激PTC细胞的体外迁移。相比之下，sirna介导的EphB3敲低或EphB3- fc处理，仅阻断EphB3介导的正向信号传导，抑制PTC细胞的迁移和转移。机制研究表明，敲低EphB3可抑制Rac1活性，增强RhoA活性。此外，我们发现Rho家族GTPases的重要调节因子Vav2被EphB3以激酶依赖的方式激活。综上所述，我们的研究表明，EphB3通过以激酶依赖的方式调节Vav2和Rho GTPases的活性，增加PTC细胞的体外迁移和体内转移，从而在PTC中发挥肿瘤启动子的作用。
Eph receptors, the largest subfamily of transmembrane tyrosine kinase receptors, have been increasingly implicated in various physiologic and pathologic processes, and the roles of the Eph family members during tumorigenesis have recently attracted growing attentions. In the present study, we explored the function of EphB3, one member of Eph family, in papillary thyroid cancer (PTC). We found that the expression of EphB3 was significantly elevated in PTC. Either overexpression of EphB3 or activation of EphB3 by EfnB1-Fc/EfnB2-Fc stimulated in vitro migration of PTC cells. In contrast, siRNA-mediated knockdown of EphB3 or EphB3-Fc treatment, which only blocked EphB3-mediated forward signaling, inhibited migration and metastasis of PTC cells. A mechanism study revealed that EphB3 knockdown led to suppressed activity of Rac1 and enhanced activity of RhoA. Moreover, we found that Vav2, an important regulator of Rho family GTPases, was activated by EphB3 in a kinase-dependent manner. Altogether, our work suggested that EphB3 acted as a tumor promoter in PTC by increasing the in vitro migration as well as the in vivo metastasis of PTC cells through regulating the activities of Vav2 and Rho GTPases in a kinase-dependent manner.