WWC3 regulates the Wnt and Hippo pathways via Dishevelled proteins and large tumour suppressor 1, to suppress lung cancer invasion and metastasis
WWC3 regulates the Wnt and Hippo pathways via Dishevelled proteins and large tumour suppressor 1, to suppress lung cancer invasion and metastasis
复制标题
WWC3通过Disheveled蛋白和大肿瘤抑制因子1调节Wnt和Hippo通路，抑制肺癌侵袭和转移
DOI：
10.1002/path.4919
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发表时间：
2017-08-01
影响因子：
7.3
通讯作者：
Wang, Enhua
中科院分区：
文献类型：
--
作者：
Han, Qiang;Lin, Xuyong;Wang, Enhua
已知支架蛋白WWC（包含WW和C2结构域）家族通过Hippo信号传导途径调节细胞增殖和器官大小。然而，WWC 3在人类肿瘤中的表达水平及其在细胞信号转导中的作用机制尚未报道。本研究旨在探讨WWC 3在肺癌细胞中的作用及其分子机制。我们发现WWC 3在肺癌细胞系和肺癌标本中的低表达，这与肺癌患者的低分化、晚期pTNM分期、阳性淋巴结转移和不良预后相关。此外，WWC 3的过表达抑制肺癌细胞的增殖和侵袭能力。这些作用分别通过体外和体内Wnt和Hippo通路的抑制和刺激介导。具体地，WWC 3与Dishevelled（Dvl）蛋白相互作用，阻止酪蛋白激酶1。使Dvl磷酸化，并抑制。- 连环蛋白核转位以抑制Wnt途径。删除WWC 3的WW和C-末端PDZ结合结构域消除了这些作用。此外，WWC 3与Dvls的相互作用降低了WWC 3与大肿瘤抑制因子1（LATS 1）之间的相互作用，以及降低LATS 1磷酸化以增加yes相关蛋白（雅普）的核输入并减弱Hippo途径。删除WWC 3的WW域消除了这种效果。这些发现证明了WWC 3、Dvls和LATS 1之间的分子相互作用，并揭示了Wnt和Hippo通路之间的联系，这为肺癌的临床干预提供了潜在的靶点。版权所有（C）2017大不列颠和爱尔兰病理学会。由John Wiley & Sons有限公司出版
The scaffolding protein WWC (WW and C2-domain containing) family is known to regulate cell proliferation and organ size via the Hippo signalling pathway. However, the expression level of WWC3 in human tumours and the mechanisms underlying its role in cellular signal transduction have not yet been reported. Herein, we explored the potential roles of WWC3 in lung cancer cells and the corresponding molecular mechanisms. We found low WWC3 expression in both lung cancer cell lines and lung cancer specimens, which was associated with low differentiation, advanced pTNM stage, positive lymph node metastasis, and poor prognosis in patients with lung cancer. Moreover, the overexpression of WWC3 inhibited the proliferation and invasiveness of lung cancer cells. These effects were mediated by the inhibition and stimulation of the Wnt and Hippo pathways, respectively, in vitro and in vivo. Specifically, WWC3 interacts with Dishevelled (Dvl) proteins, prevents casein kinase 1. from phosphorylating Dvls, and inhibits. -catenin nuclear translocation to inhibit the Wnt pathway. Deleting the WW and C-terminal PDZ-binding domains of WWC3 abrogated these effects. Moreover, the interaction of WWC3 with Dvls reduced the interaction between WWC3 and large tumour suppressor 1 (LATS1), as well as decreasing LATS1 phosphorylation to increase the nuclear importation of yes-associated protein (YAP) and attenuate the Hippo pathway. Deleting the WW domain of WWC3 abrogated this effect. These findings demonstrate the molecular interplay between WWC3, Dvls, and LATS1, and reveal a link between the Wnt and Hippo pathways, which provides a potential target for clinical intervention in lung cancer. Copyright (C) 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.