SHP-2-upregulated ZEB1 is important for PDGFRα-driven glioma epithelial-mesenchymal transition and invasion in mice and humans.
SHP-2-upregulated ZEB1 is important for PDGFRα-driven glioma epithelial-mesenchymal transition and invasion in mice and humans.
复制标题
SHP-2 上调的 ZEB1 对于 PDGFRα 驱动的小鼠和人类神经胶质瘤上皮间质转化和侵袭非常重要。
作者：
神经胶质瘤是高度恶性的脑肿瘤，具有高度侵袭性并且对常规治疗具有抗性。受体酪氨酸激酶（RTK），如PDGFRα（血小板源性生长因子受体-α），在胶质瘤中显示频繁的异常激活，与上皮-间质转化（EMT）过程相关，EMT是一种赋予更具侵袭性和耐药性表型的细胞改变。尽管这种现象在人类癌症中得到了很好的证明，但包括PDGFRα在内的RTK介导EMT的过程在很大程度上是未知的。在这里，我们报告了SHP-2（由PTPN 11编码）上调EMT诱导剂ZEB 1，以介导PDGFRα驱动的胶质瘤EMT，使用细胞培养和原位异种移植模型在胶质瘤细胞系和患者源性胶质瘤干细胞（GSC）中的侵袭和生长。ZEB 1和活化的PDGFRα在小鼠胶质瘤异种移植物和临床胶质瘤标本的侵袭区共表达。与p-PDGFRα和ZEB 1低表达的胶质瘤患者相比，磷酸化PDGFR α（p-PDGFRα）和ZEB 1高水平的胶质瘤患者的总生存期显著缩短。ZEB 1的敲低抑制了PDGFA/PDGFRα刺激的胶质瘤EMT、胶质瘤细胞系和患者源性GSC中的肿瘤生长和侵袭。缺乏SHP 2结合（PDGFRα-F720）或磷酸肌醇3-激酶（PI 3 K）结合（PDGFRα-F731/42）的PDGFRα突变体、SHP 2敲低或PDGFRα信号传导效应物的药理学抑制剂治疗可减弱PDGFA/PDGFRα刺激的ZEB 1表达、细胞迁移和GSC增殖。重要的是，SHP-2与PI 3 K/AKT一起调节PDGFRα驱动的胶质瘤中的ZEB 1-miR-200反馈环。总之，我们的研究结果揭示了一条新的途径，其中ZEB 1作为PDGFRα驱动的胶质瘤EMT，侵袭性和生长的关键调节因子发挥作用，这表明ZEB 1是治疗具有高PDGFRα活化的胶质瘤的有希望的治疗靶点。
Gliomas are highly malignant brain tumors that are highly invasive and resistant to conventional therapy. Receptor tyrosine kinases (RTKs) such as PDGFRα (platelet-derived growth factor receptor-α), which show frequent aberrant activation in gliomas, are associated with a process of epithelial–mesenchymal transition (EMT), a cellular alteration that confers a more invasive and drug-resistant phenotype. Although this phenomenon is well documented in human cancers, the processes by which RTKs including PDGFRα mediate EMT are largely unknown. Here, we report that SHP-2 (encoded by PTPN11) upregulates an EMT inducer, ZEB1, to mediate PDGFRα-driven glioma EMT, invasion and growth in glioma cell lines and patient-derived glioma stem cells (GSCs) using cell culture and orthotopic xenograft models. ZEB1 and activated PDGFRα were coexpressed in invasive regions of mouse glioma xenografts and clinical glioma specimens. Glioma patients with high levels of both phospho-PDGFRα (p-PDGFRα) and ZEB1 had significantly shorter overall survival compared with those with low expression of p-PDGFRα and ZEB1. Knockdown of ZEB1 inhibited PDGFA/PDGFRα-stimulated glioma EMT, tumor growth and invasion in glioma cell lines and patient-derived GSCs. PDGFRα mutant deficient of SHP2 binding (PDGFRα-F720) or phosphoinositide 3-kinase (PI3K) binding (PDGFRα-F731/42), knockdown of SHP2 or treatments of pharmacological inhibitor for PDGFRα-signaling effectors attenuated PDGFA/PDGFRα-stimulated ZEB1 expression, cell migration and GSC proliferation. Importantly, SHP-2 acts together with PI3K/AKT to regulate a ZEB1-miR-200 feedback loop in PDGFRα-driven gliomas. Taken together, our findings uncover a new pathway in which ZEB1 functions as a key regulator for PDGFRα-driven glioma EMT, invasiveness and growth, suggesting that ZEB1 is a promising therapeutic target for treating gliomas with high PDGFRα activation.
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