A miR-135b-TAZ positive feedback loop promotes epithelial-mesenchymal transition (EMT) and tumorigenesis in osteosarcoma
A miR-135b-TAZ positive feedback loop promotes epithelial-mesenchymal transition (EMT) and tumorigenesis in osteosarcoma
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DOI：
10.1016/j.canlet.2017.08.005
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发表时间：
2017-10-28
期刊：
影响因子：
9.7
通讯作者：
Ma, Jianjun
中科院分区：
文献类型：
--
作者：
Shen, Shuying;Huang, Kangmao;Ma, Jianjun
具有PDZ结合基序的转录共激活因子（TAZ）是一种含有WW结构域的蛋白，其调节间充质分化和器官发育。它也是Hippo信号通路的下游效应物，其与上皮间质转化（EMT）和肿瘤发生有关。然而，TAZ在骨肉瘤（OS）中这些过程中的分子机制还不清楚。我们在本研究中使用U2 OS和HOS细胞系解决了这一问题。我们发现，TAZ信号是通过一个以前未描述的微（mi）RNA依赖性正反馈回路来维持的。由TAZ直接诱导的miRNA miR-135 b抑制TAZ抑制剂大肿瘤抑制因子2、腺瘤性结肠息肉病和糖原合成酶激酶30，从而放大TAZ信号传导并诱导EMT。miR-135 b的过表达引起TAZ的组成性激活，这挽救了由TAZ敲低诱导的细胞增殖和EMT抑制。这些结果提供了TAZ和miR-135 b参与正反馈回路以调节OS中的EMT和转移的证据，并表明这两种因子可以成为OS治疗的治疗靶点。(C)2017爱思唯尔B. V.保留所有权利。
Transcriptional co-activator with PDZ-binding motif (TAZ) is a WW domain-containing protein that regulates mesenchymal differentiation and organ development. It is also a downstream effector of the Hippo signaling pathway, which has been implicated in epithelial mesenchymal transition (EMT) and tumorigenesis. However, the molecular mechanisms underlying TAZ function in these processes in the context of osteosarcoma (OS) are not well understood. We addressed this in the present study using U2OS and HOS cell lines. We found that TAZ signaling is maintained via a previously undescribed micro (mi)RNA-dependent positive feedback loop. The miRNA miR-135b, which is directly induced by TAZ, suppressed the TAZ inhibitors large tumor suppressor 2, adenomatous polyposis coli, and glycogen synthase kinase 30, thereby amplifying TAZ signaling and inducing EMT. Overexpression of miR-135b caused constitutive activation of TAZ, which rescued the inhibition of cell proliferation and EMT induced by TAZ knockdown. These results provide evidence that TAZ and miR-135b engage in a positive feedback loop to regulate EMT and metastasis in OS, and suggest that both factors can be therapeutic targets for OS treatment. (C) 2017 Elsevier B.V. All rights reserved.