In vitro study of FUZ as a novel potential therapeutic target in non-small-cell lung cancer
In vitro study of FUZ as a novel potential therapeutic target in non-small-cell lung cancer
复制标题
FUZ 作为非小细胞肺癌新型潜在治疗靶点的体外研究
DOI：
10.1016/j.lfs.2018.02.007
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发表时间：
2018-03-15
期刊：
影响因子：
6.1
通讯作者：
Wang, Lu
中科院分区：
文献类型：
--
作者：
He, Minwei;Li, Kangqi;Wang, Lu
FUZ被认为是一个平面细胞极性效应器，在脊椎动物发育过程中控制多个细胞过程。然而，FUZ在肿瘤生物学中的作用仍然研究甚少。本研究的目的是探讨FUZ对体外培养的非小细胞肺癌（NSCLC）细胞的生理作用及其机制。通过生物信息学分析发现，FUZ的表达水平与NSCLC患者的预后呈负相关。外源性FUZ基因表达可明显促进NSCLC细胞增殖。FUZ过表达后，Erk 1/2、STAT 3及相关信号分子的磷酸化被激活。FUZ还通过调节细胞信号传导途径和诱导上皮向间充质转化（EMT）在细胞运动中起重要作用。FUZ促进EMT沿着N-cadherin、vimentin、Zeb 1、Twist 1表达上调，E-cadherin表达降低。此外，我们还进行了FUZ定向siRNA处理以证明上述观察结果。敲除FUZ导致细胞生长延迟以及细胞迁移受损和EMT表型逆转。重要的是，我们首次报道了FUZ是一种BNIP 3相互作用蛋白。FUZ缺失导致BNIP 3蛋白水平降低，但对BNIP 3 mRNA水平无影响，提示BNIP 3蛋白稳定性减弱。总体而言，我们的体外研究结果表明，FUZ是NSCLC进展和转移的原因，这表明FUZ可能是NSCLC的潜在治疗靶点。
FUZ is regarded as a planar cell polarity effector that controls multiple cellular processes during vertebrate development. However, the role of FUZ in tumor biology remains poorly studied. Our purpose of this study is to discover the physiological effects and mechanism of FUZ in non-small-cell lung cancer (NSCLC) in vitro. With the help of bioinformatics analysis, we noticed that the expression level of FUZ negatively correlates with prognosis of NSCLC patients. Exogenous FUZ expression markedly promoted cell proliferation of NSCLC cells. The phosphorylation of Erk1/2, STAT3 and related signaling molecules were induced activated after FUZ over-expression. FUZ also plays an important role in cell motility by regulating cell signaling pathways and inducing epithelial to mesenchymal transition (EMT). FUZ promotes EMT along with the up-regulation of N-cadherin, vimentin, Zeb1, Twist1 and decreased level of E-cadherin. Furthermore, we also carried out FUZ directed siRNA treatments to prove the above observations. Knockdown of FUZ resulted in delayed cell growth as well as impaired cell migration and reversed EMT phonotype. Importantly, we reported for the first time that FUZ is a BNIP3-interacting protein. Loss of FUZ resulted in decreased BNIP3 protein level, but no influence on BNIP3 mRNA level, suggesting weakened stability of BNIP3 protein. Overall, our results in vitro show that FUZ is responsible for NSCLC progression and metastasis, suggesting that FUZ can be a potential therapeutic target for NSCLC.