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首页> 外文期刊>Oncogene >Imipramine blue halts head and neck cancer invasion through promoting F-box and leucine-rich repeat protein 14-mediated Twist1 degradation
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Imipramine blue halts head and neck cancer invasion through promoting F-box and leucine-rich repeat protein 14-mediated Twist1 degradation

机译：丙咪嗪蓝通过促进 F-box 和富含亮氨酸的重复蛋白 14 介导的 Twist1 降解来阻止头颈癌的侵袭

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摘要

The unique characteristic of head and neck squamous cell carcinoma (HNSCC) is that local invasion rather than distant metastasis is the major route for dissemination. Therefore, targeting the locally invasive cancer cells is more important than preventing systemic metastasis in HNSCC and other invasive-predominant cancers. We previously demonstrate a specific mechanism for HNSCC local invasion: the epithelial-mesenchymal transition (EMT) regulator Twist1 represses microRNA let-7i expression, leading to the activation of the small GTPase Rac1 and engendering the mesenchymal-mode movement in three-dimensional (3D) culture. However, targeting the EMT regulator is relatively difficult because of its transcription factor nature and the strategy for confining HNSCC invasion to facilitate local treatment is limited. Imipramine blue (IB) is a newly identified anti-invasive compound that effectively inhibits glioma invasion. Here we demonstrate that in HNSCC cells, a noncytotoxic dose of IB represses mesenchymal-mode migration in two-and-a-half-dimensional/3D culture system. IB suppresses EMT and stemness of HNSCC cells through inhibition of Twist1-mediated let-7i downregulation and Rac1 activation and the EMT signalling. Mechanistically, IB inhibits reactive oxygen species-induced nuclear factor-kappa B pathway activation. Importantly, IB promotes degradation of the EMT inducer Twist1 by enhancing F-box and leucine-rich repeat protein 14 (FBXL14)-mediated polyubiquitination of Twist1. Together, this study demonstrates the potent anti-invasion and EMT-inhibition effect of IB, suggesting the potential of IB in treating local invasion-predominant cancers.
机译：头颈部鳞状细胞癌（HNSCC）的独特之处在于，局部浸润而非远处转移是主要的播散途径。因此，靶向局部浸润性癌细胞比预防HNSCC和其他侵袭性优势癌症的全身转移更重要。我们之前证明了HNSCC局部侵袭的特定机制：上皮-间充质转化（EMT）调节因子Twist1抑制microRNA let-7i表达，导致小GTP酶Rac1的激活，并在三维（3D）培养中产生间充质模式运动。然而，由于EMT调节因子的转录因子性质，靶向EMT调节因子相对困难，并且限制HNSCC侵袭以促进局部治疗的策略有限。丙咪嗪蓝（IB）是一种新发现的抗侵袭性化合物，可有效抑制胶质瘤侵袭。在这里，我们证明在HNSCC细胞中，无细胞毒性剂量的IB抑制了二维半/ 3D培养系统中的间充质模式迁移。IB 通过抑制 Twist1 介导的 let-7i 下调和 Rac1 激活以及 EMT 信号传导来抑制 HNSCC 细胞的 EMT 和干性。从机制上讲，IB 抑制活性氧诱导的核因子-κB 通路激活。重要的是，IB 通过增强 F-box 和富含亮氨酸的重复蛋白 14 （FBXL14） 介导的 Twist1 多泛素化来促进 EMT 诱导剂 Twist1 的降解。总之，这项研究证明了IB的强效抗侵袭和EMT抑制作用，表明IB在治疗局部侵袭性癌症方面的潜力。

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  • 来源
    《Oncogene》 |2016年第18期|2287-2298|共12页
  • 作者

    Yang W-H; Su Y-H; Hsu W-HWang C-CArbiser J. L.Yang M-H;

  • 作者单位

    Natl Yang Ming Univ, Inst Clin Med, 155,Sec 2,Li Nong St, Taipei 11221, Taiwan;

    Taichung Vet Gen Hosp, Dept Otolaryngol Head & Neck Surg, Taichung, Taiwan;

    Emory Sch Med, Dept Dermatol, Atlanta, GA USA;

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  • 正文语种 英语
  • 中图分类 肿瘤学;
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