Tan Xiaochao, Banerjee Priyam, Guo Hou-Fu, Ireland Stephen, Pankova Daniela, Ahn Young-Ho, Nikolaidis Irodotos Michail, Liu Xin, Zhao Yanbin, Xue Yongming, Burns Alan R, Roybal Jonathon, Gibbons Don L, Zal Tomasz, Creighton Chad J, Ungar Daniel, Wang Yanzhuang, Kurie Jonathan M
J Clin Invest. 2017 Jan 3;127(1):117-131. doi: 10.1172/JCI88736. Epub 2016 Nov 21.
Tumor cells gain metastatic capacity through a Golgi phosphoprotein 3-dependent (GOLPH3-dependent) Golgi membrane dispersal process that drives the budding and transport of secretory vesicles. Whether Golgi dispersal underlies the pro-metastatic vesicular trafficking that is associated with epithelial-to-mesenchymal transition (EMT) remains unclear. Here, we have shown that, rather than causing Golgi dispersal, EMT led to the formation of compact Golgi organelles with improved ribbon linking and cisternal stacking. Ectopic expression of the EMT-activating transcription factor ZEB1 stimulated Golgi compaction and relieved microRNA-mediated repression of the Golgi scaffolding protein PAQR11. Depletion of PAQR11 dispersed Golgi organelles and impaired anterograde vesicle transport to the plasma membrane as well as retrograde vesicle tethering to the Golgi. The N-terminal scaffolding domain of PAQR11 was associated with key regulators of Golgi compaction and vesicle transport in pull-down assays and was required to reconstitute Golgi compaction in PAQR11-deficient tumor cells. Finally, high PAQR11 levels were correlated with EMT and shorter survival in human cancers, and PAQR11 was found to be essential for tumor cell migration and metastasis in EMT-driven lung adenocarcinoma models. We conclude that EMT initiates a PAQR11-mediated Golgi compaction process that drives metastasis.
肿瘤细胞通过一种依赖高尔基体磷蛋白3（GOLPH3）的高尔基体膜分散过程获得转移能力，该过程驱动分泌囊泡的出芽和运输。高尔基体分散是否是与上皮-间充质转化（EMT）相关的促转移囊泡运输的基础仍不清楚。在这里，我们已经表明，EMT并没有导致高尔基体分散，而是导致了紧密的高尔基体细胞器的形成，其带状连接和潴泡堆叠得到改善。EMT激活转录因子ZEB1的异位表达刺激了高尔基体的压实，并解除了微小RNA介导的对高尔基体支架蛋白PAQR11的抑制。PAQR11的缺失使高尔基体细胞器分散，并损害了向质膜的顺行囊泡运输以及向高尔基体的逆行囊泡拴系。在下拉试验中，PAQR11的N端支架结构域与高尔基体压实和囊泡运输的关键调节因子相关，并且是在PAQR11缺陷的肿瘤细胞中重建高尔基体压实所必需的。最后，PAQR11的高表达水平与人类癌症中的EMT和较短生存期相关，并且发现在EMT驱动的肺腺癌模型中PAQR11对于肿瘤细胞迁移和转移至关重要。我们得出结论，EMT启动了一个由PAQR11介导的高尔基体压实过程，该过程驱动转移。
