Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells
Hypoxia-Induced WSB1 Promotes the Metastatic Potential of Osteosarcoma Cells
复制标题
缺氧诱导的WSB1促进骨肉瘤细胞的转移潜能
DOI：
10.1158/0008-5472.can-15-0711
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发表时间：
2015-11-15
期刊：
影响因子：
11.2
通讯作者：
Yang, Bo
中科院分区：
文献类型：
--
作者：
Cao, Ji;Wang, Yijie;Yang, Bo
瘤内缺氧发生在许多实体瘤中，其与转移性特征的发展相关。然而，这些现象之间的联系还没有得到充分的理解。在这项研究中，我们定义了E3泛素连接酶亚基WSB 1的整合作用。在原发性骨肉瘤中，WSB 1水平升高与肺转移潜能相关。RNAi介导的WSB 1的衰减或其E3连接酶活性的破坏有效地抑制了肿瘤转移。定量蛋白质组学和功能分析表明，WSB 1泛素化的Rho结合蛋白RhoGDI2，并促进其蛋白酶体降解，从而激活Rac 1刺激肿瘤细胞的运动和侵袭。我们的研究结果显示了WSB 1如何调节缺氧驱动的骨肉瘤转移级联反应的关键步骤，并且它们突出了一个候选治疗靶点，可能改善转移性疾病患者的生存率。(C)2015年AACR。
Intratumoral hypoxia occurs in many solid tumors, where it is associated with the development of metastatic character. However, the connections between these phenomena are not fully understood. In this study, we define an integrative role for the E3 ubiquitin ligase subunit WSB1. In primary osteosarcomas, increased levels of WSB1 correlated with pulmonary metastatic potential. RNAi-mediated attenuation of WSB1 or disruption of its E3 ligase activity potently suppressed tumor metastasis. Quantitative proteomic and functional analyses revealed that WSB1 ubiquitylates the Rho-binding protein RhoGDI2 and promotes its proteasomal degradation, thereby activating Rac1 to stimulate tumor cell motility and invasion. Our findings show how WSB1 regulates key steps of the metastatic cascade in hypoxia-driven osteosarcoma, and they highlight a candidate therapeutic target to potentially improve the survival of patients with metastatic disease. (C) 2015 AACR.