Department of Orthopaedic Surgery, Sir Run Run Shaw Hospital, Medical College of Zhejiang University, Sir Run Run Shaw Institute of Clinical Medicine of Zhejiang University, 3 East Qingchun Road, Hangzhou, Zhejiang Province, 310016, China.
School of Computer Science and Technology, Hangzhou Dianzi University, 310018, China.
Cancer Lett. 2017 Oct 28;407:32-44. doi: 10.1016/j.canlet.2017.08.005. Epub 2017 Aug 18.
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 3β, 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.
转录共激活因子含有 PDZ 结合基序（TAZ）是一种 WW 结构域蛋白，可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，该通路与上皮-间充质转化（EMT）和肿瘤发生有关。然而，TAZ 在骨肉瘤（OS）背景下这些过程中的功能的分子机制尚不清楚。我们使用 U2OS 和 HOS 细胞系在本研究中解决了这个问题。我们发现 TAZ 信号通过以前未描述的 micro（mi）RNA 依赖性正反馈环维持。miR-135b 可被 TAZ 直接诱导，抑制 TAZ 抑制剂大肿瘤抑制因子 2、结肠腺瘤性息肉病和糖原合成酶激酶 3β，从而放大 TAZ 信号并诱导 EMT。miR-135b 的过表达导致 TAZ 的组成性激活，这挽救了 TAZ 敲低诱导的细胞增殖和 EMT 抑制。这些结果表明，TAZ 和 miR-135b 参与正反馈环以调节 OS 中的 EMT 和转移，并表明这两个因素都可以成为 OS 治疗的治疗靶点。
