SHROOM2 inhibits tumor metastasis through RhoA–ROCK pathway-dependent and -independent mechanisms in nasopharyngeal carcinoma
SHROOM2 inhibits tumor metastasis through RhoA–ROCK pathway-dependent and -independent mechanisms in nasopharyngeal carcinoma
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DOI：
10.1038/s41419-019-1325-7
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发表时间：
2019-01
影响因子：
9
通讯作者：
Jing Yuan;Lin Chen;Jingshu Xiao;Xue-Kang Qi;Ji Zhang;Xu Li;Zifeng Wang;Yi-Fan Lian;T. Xiang;Yu-Chen Zhang;Ming-Yuan Chen;J. Bei;Y. Zeng;Lin Feng
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文献类型：
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作者：
Jing Yuan;Lin Chen;Jingshu Xiao;Xue-Kang Qi;Ji Zhang;Xu Li;Zifeng Wang;Yi-Fan Lian;T. Xiang;Yu-Chen Zhang;Ming-Yuan Chen;J. Bei;Y. Zeng;Lin Feng
SHROOM 2是RhoA-ROCK通路的关键介质，调节细胞运动和肌动蛋白细胞骨架组织。然而，除了RhoA/ROCK信号传导之外，SHROOM 2的功能仍然知之甚少。在这里，我们报告说，SHROOM 2不仅参与RhoA-ROCK诱导的应力纤维的形成和粘着斑，但也有一个意想不到的作用，抑制上皮间质转化（EMT）和肿瘤转移。鼻咽癌（NPC）细胞中SHR 00 M2的消耗增强间充质特征并减少上皮标志物，伴随增加的运动性，使得侵袭和肿瘤转移的发展成为可能，这在很大程度上是ROCK非依赖性的，因为ROCK抑制剂Y-27632不引起EMT表型;此外，ROCK抑制和SHROOM 2消耗的组合导致细胞迁移和侵袭的最强有力的增加，表明SHROOM 2和ROCK协同作用而不是上位作用。对临床标本的分析表明，SHROOM 2在NPC中表达下调，转移性NPC中SHROOM 2的表达甚至低于原发性肿瘤。我们的研究结果揭示了SHROOM 2作为EMT和NPC转移的有效拮抗剂的非经典作用。
SHROOM2 is a key mediator of RhoA–ROCK pathway that regulates cell motility and actin cytoskeleton organization. However, the functions of SHROOM2 beyond RhoA/ROCK signaling remain poorly understood. Here, we report that SHROOM2 not only participates in RhoA–ROCK-induced stress fiber formation and focal adhesion, but also had an unanticipated role in suppressing epithelial-to-mesenchymal transition (EMT) and tumor metastasis. Depletion of SHROOM2 in nasopharyngeal carcinoma (NPC) cells enhances mesenchymal characteristics and reduces epithelial markers, concomitant with increased motility, enabling the development of invasion and tumor metastasis, which are largely ROCK-independent, as ROCK inhibitor Y-27632 did not cause EMT phenotype; furthermore, combination of ROCK inhibition and SHROOM2 depletion resulted in the most robust increases in cell migration and invasion, indicating that SHROOM2 and ROCK work synergistically rather than epistatic. Analysis of clinical samples suggested that SHROOM2 is downregulated in NPC and the expression of SHROOM2 in metastatic NPC was even lower than in the primary tumors. Our findings uncover a non-canonical role of SHROOM2 as a potent antagonist for EMT and NPC metastasis.