Ma Xianjue, Wang Hongxiang, Ji Jiansong, Xu Wenyan, Sun Yihao, Li Wenzhe, Zhang Xiaoping, Chen Juxiang, Xue Lei
Institute of Intervention Vessel, Shanghai 10th People's Hospital, Shanghai Key Laboratory of Signaling and Disease Research, School of Life Science and Technology, Tongji University, Shanghai 200092, China;
Department of Genetics, Yale School of Medicine, New Haven, CT 06536.
Proc Natl Acad Sci U S A. 2017 Feb 21;114(8):1934-1939. doi: 10.1073/pnas.1621359114. Epub 2017 Feb 7.
Overwhelming studies show that dysregulation of the Hippo pathway is positively correlated with cell proliferation, growth, and tumorigenesis. Paradoxically, the detailed molecular roles of the Hippo pathway in cell invasion remain debatable. Using a invasion model in wing epithelium, we show herein that activated Hippo signaling promotes cell invasion and epithelial-mesenchymal transition through JNK, as inhibition of JNK signaling dramatically blocked Hippo pathway activation-induced matrix metalloproteinase 1 expression and cell invasion. Furthermore, we identify -Rox8 modules as essential components downstream of Yorkie in mediating JNK-dependent cell invasion. Finally, we confirm that YAP (Yes-associated protein) expression negatively regulates TIA1 (Rox8 ortholog) expression and cell invasion in human cancer cells. Together, these findings provide molecular insights into Hippo pathway-mediated cell invasion and also raise a noteworthy concern in therapeutic interventions of Hippo-related cancers, as simply inhibiting Yorkie or YAP activity might paradoxically accelerate cell invasion and metastasis.
大量研究表明，Hippo信号通路的失调与细胞增殖、生长和肿瘤发生呈正相关。矛盾的是，Hippo信号通路在细胞侵袭中的详细分子作用仍存在争议。利用翅上皮的侵袭模型，我们在此表明，激活的Hippo信号通过JNK促进细胞侵袭和上皮-间质转化，因为抑制JNK信号显著阻断了Hippo信号通路激活诱导的基质金属蛋白酶1表达和细胞侵袭。此外，我们确定-Rox8模块是Yorkie下游介导JNK依赖性细胞侵袭的必需成分。最后，我们证实YAP（Yes相关蛋白）表达在人类癌细胞中负向调节TIA1（Rox8直系同源物）表达和细胞侵袭。总之，这些发现为Hippo信号通路介导的细胞侵袭提供了分子见解，也在Hippo相关癌症的治疗干预中引发了一个值得关注的问题，因为简单地抑制Yorkie或YAP活性可能会反常地加速细胞侵袭和转移。
