Gankyrin promotes osteosarcoma tumorigenesis by forming a positive feedback loop with YAP
Gankyrin promotes osteosarcoma tumorigenesis by forming a positive feedback loop with YAP
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Gankyrin 通过与 YAP 形成正反馈环促进骨肉瘤肿瘤发生
DOI：
10.1016/j.cellsig.2019.109460
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发表时间：
2020-01-01
影响因子：
4.8
通讯作者：
Xiong, Zhigang
中科院分区：
文献类型：
--
作者：
Cheng, Li;Wu, Baoming;Xiong, Zhigang
背景资料：方法：采用定量RT-PCR、免疫印迹和免疫组化染色方法检测Gankyrin在骨肉瘤（osteosarcoma，OS）中的表达，采用Pearson χ 2检验分析Gankyrin表达与临床病理特征的关系。Kaplan-Meier方法被用来调查Gankyrin的表达和OS患者的总生存期之间的关系。接下来，一系列的在体外和体内试验进行，以确定Gankyrin和雅普在OS中的正反馈回路。结果：我们首次报道，Gankyrin在人类OS标本和细胞系上调，并预测OS进展和预后不良。此外，我们证明Gankyrin通过p53保护miR-200 a介导的yes相关蛋白（雅普）下调，并建立了一个正反馈环来调节U2 OS和MG 63细胞中的雅普信号传导。有趣的是，Gankyrin与雅普相互作用以促进体外OS细胞生长。此外，我们的研究结果表明，Gankyrin促进OS肿瘤生长和调节体内雅普水平。值得注意的是，我们还观察到gankyrin和雅普在人类OS组织中的表达之间的正相关性，并且gankyrin和雅普的共上调表明预后不良。结论：我们的研究结果确定，gankyrin作为一种癌基因在OS中通过与雅普形成正反馈环，并且破坏gankyrin-雅普调节可能有利于控制OS肿瘤发生。
Background: Although gankyrin has been identified as a vital regulator of tumorigenesis, its role and regulatory mechanism in osteosarcoma (OS) remain unclear.Methods: QRT-PCR, western blot and IHC staining were conducted to detect the expression of gankyrin in OS. Pearson's chi(2) test was adopted to examine the associations between gankyrin expression and clinicopathologic characteristics. Kaplan-Meier method was used to investigate the relationship between gankyrin expression and overall survival of patients with OS. Next, a series of in vitro and in vivo assays were performed to determine the positive feedback loop between gankyrin and YAP in OS.Results: We first reported that gankyrin is upregulated in human OS specimens and cell lines and predicts OS progression and poor prognosis. Furthermore, we demonstrated that gankyrin protects miR-200a-mediated yes-associated protein (YAP) downregulation through p53 and establishes a positive feedback loop to regulate YAP signaling in U2OS and MG63 cells. Intriguingly, gankyrin interacts with YAP to promote OS cell growth in vitro. In addition, our results showed that gankyrin promotes OS tumor growth and regulates YAP levels in vivo. Notably, we also observed a positive correlation between gankyrin and YAP expression in human OS tissues, and co-upregulation of gankyrin and YAP indicated a poor prognosis.Conclusions: Our results identify that gankyrin acts as an oncogene in OS by forming a positive feedback loop with YAP, and disrupting the gankyrin-YAP regulation may be beneficial for controlling OS tumorigenesis.