LATS1/2 kinases trigger self-renewal of cancer stem cells in aggressive oral cancer.
LATS1/2 kinases trigger self-renewal of cancer stem cells in aggressive oral cancer.
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DOI：
10.18632/oncotarget.26583
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发表时间：
2019-02-01
期刊：
影响因子：
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通讯作者：
Nojima, Hiroshi
中科院分区：
文献类型：
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作者：
Nozaki, Masami;Yabuta, Norikazu;Nojima, Hiroshi
肿瘤干细胞（CSCs）在肿瘤的发生和发展中起着重要作用，对许多类型的治疗具有耐药性。然而，csc特异性特性（包括自我更新）的调控机制尚不清楚。在这里，我们发现核心Hippo通路激酶LATS1/2在口腔鳞状细胞癌细胞系SAS中高表达，而SAS具有较高的CSCs容量，并且这些激酶的耗尽阻止了SAS细胞在无血清条件下形成球。对LATS激酶和相关蛋白在球形成过程中的表达和激活的详细检查表明，在自我更新开始之前，LATS1/2的表达和激活程度更高。此外，TAZ， SNAIL， CHK1/2和Aurora-A在球体形成过程中以分层振荡模式表达，表明该过程由四个连续步骤组成。我们的研究结果表明，LATS1/2通过调节Hippo通路、EMT和细胞分裂来触发CSCs的自我更新。
Cancer stem cells (CSCs), which play important roles in tumor initiation and progression, are resistant to many types of therapies. However, the regulatory mechanisms underlying CSC-specific properties, including self-renewal, are poorly understood. Here, we found that LATS1/2, the core Hippo pathway-kinases, were highly expressed in the oral squamous cell carcinoma line SAS, which exhibits high capacity of CSCs, and that depletion of these kinases prevented SAS cells from forming spheres under serum-free conditions. Detailed examination of the expression and activation of LATS kinases and related proteins over a time course of sphere formation revealed that LATS1/2 were more highly expressed and markedly activated before initiation of self-renewal. Moreover, TAZ, SNAIL, CHK1/2, and Aurora-A were expressed in hierarchical, oscillating patterns during sphere formation, suggesting that the process consists of four sequential steps. Our results indicate that LATS1/2 trigger self-renewal of CSCs by regulating the Hippo pathway, the EMT, and cell division.