Activation of STAT1 by the FRK tyrosine kinase is associated with human glioma growth
Activation of STAT1 by the FRK tyrosine kinase is associated with human glioma growth
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FRK 酪氨酸激酶激活 STAT1 与人神经胶质瘤生长相关
DOI：
10.1007/s11060-019-03143-w
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发表时间：
2019-05-01
影响因子：
3.9
通讯作者：
Yu, Rutong
中科院分区：
文献类型：
--
作者：
Hua, Lei;Wang, Guanghui;Yu, Rutong
目的胶质瘤是一种高度侵袭性和致死性的脑肿瘤。信号转导和转录激活因子（STAT）通路广泛参与胶质瘤的发生发展。我们前期的研究发现，Fynrelated kinase（FRK）基因在胶质瘤的发生发展中起着抑癌作用。本研究旨在探讨FRK在STATs活化途径中的作用及其对胶质瘤生长的影响。Western blotting检测FRK对STAT信号通路相关蛋白的影响。免疫共沉淀法检测FRK与STAT 1的结合。采用CCK-8和Edu细胞增殖实验检测STAT 1对胶质瘤细胞增殖的影响。采用免疫印迹法和免疫组化法检测FRK和p-STAT 1在胶质瘤组织中的表达及相关性。结果在U251和U87细胞中，过表达FRK后，p-JAK 2和p-STAT 1的表达水平升高，而下调FRK后，p-JAK 2和p-STAT 1的表达水平降低。然而，FRK对STAT 3磷酸化没有影响。ERK诱导的STAT 1激活不依赖于JAK 2。FRK与STAT 1相关，可诱导STAT 1核转位，并调节STAT 1相关靶基因的表达。STAT 1过表达可抑制胶质瘤细胞的增殖。相反，STAT 1的siRNA敲低促进胶质瘤细胞的生长。重要的是，STAT 1的下调部分减弱了FRK诱导的生长抑制。基于临床标本的研究表明，FRK的表达与p-STAT 1的表达显著相关。结论FRK通过促进STAT 1的活化而发挥抑瘤作用，为胶质瘤的治疗提供了一个潜在的靶点。
PurposeGlioma is a highly aggressive and lethal brain tumor. Signal transducers and activators of transcription (STAT) pathway are widely implicated in glioma carcinogenesis. Our previous study found that the Fynrelated kinase (FRK) gene, plays as a tumor suppressor in the development and progression of glioma. This study aimed to investigate the role of FRK in the activation pathway of STATs and its effect on the growth of glioma.MethodsThe U251 and U87 cells with stable FRK overexpression were generated by lentivirus technique. The effects of FRK on the related proteins of STAT signaling pathway were detected by western blotting. Coimmunoprecipitation was used to detect the association of FRK and STAT1. The effects of STAT1 on the proliferation of glioma cells were detected by CCK8 or Edu cell proliferation assays. The expressions and correlation of FRK and p-STAT1 in glioma tissues were detectd by western blotting or immunohistochemistry. The effect of FRK on the growth of glioma was investigated in vivo mouse model.ResultsThe level of p-JAK2 and p-STAT1 increased after FRK overexpression, while they decreased after FRK downregulation both in U251 and U87 cells. However, FRK had no effect on STAT3 phosphorylation. FRK-induced STAT1 activation was not dependent on JAK2. FRK associated with STAT1, induced STAT1 nuclear translocation and regulated the expressions of STAT1-related target genes. STAT1 overexpression suppressed the proliferation of glioma cells. In contrast, STAT1 knockdown by siRNA promoted glioma cell growth. Importantly, down-regulation of STAT1 partially attenuated FRK-induced growth suppression. The clinical sample-based study indicated that the expression of FRK was significantly correlated with the expression of p-STAT1. FRK significantly inhibited glioma tumor growth in vivo.ConclusionsOur findings highlighted a critical role of FRK in tumor suppression ability through promoting STAT1 activation, and provided a potential therapeutic target for glioma.