【摘 要】
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A critical clinical challenge in glioblastoma therapy is robust tumor growth and invasion driven by aberrant activation of oncogenic tyrosine receptor kinas
【机 构】
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StateKeyLaboratoryofOncogenesandRelatedGenes,Renji-MedXClinicalStemCellResearchCenter,RenJiHospital,
论文部分内容阅读
A critical clinical challenge in glioblastoma therapy is robust tumor growth and invasion driven by aberrant activation of oncogenic tyrosine receptor kinases (RTKs) including PDGFRalpha.Here, we report that a SHP-2-upregulated epithelial-mesenchymal transition (EMT)-inducer, ZEB 1 is important for PDGFRalpha-driven glioma EMT, invasion and glioma stem cell renewal in mice and humans.ZEB1 and activated PDGFRalpha were co-expressed in invasive regions of mouse glioma xenografts and human clinical glioma specimens.Glioma patients with high levels of both p-PDGFRalpha and ZEB1 had significantly shorter overall survival compared with those with low expression of p-PDGFRalpha and ZEB1.Knockdown of ZEB1 inhibited PDGF-A/PDGFRalpha-stimulated glioma EMT,tumor growth, invasion and glioma stem cell renewal.PDGFRalpha mutant deficient of SHP-2-binding (PDGFRalpha-F720) or PI3K binding (PDGFRalpha-F731/42), knockdown of SHP-2 or treatments of pharmacological inhibitor for PDGFR alpha-signaling effectors attenuated PDGF-A/PDGFR-stimulated ZEB1 expression, cell migration and glioma stem cell proliferation.Importantly, SHP-2 acts together with PI3K/Akt to regulate a ZEB1-miR-200 feedback loop in PDGFRalpha-driven gliomas.Together, our findings uncover a new pathway in which ZEB1 functions as a key regulator for PDGFRalpha-driven glioma EMT, invasion and glioma stem cell renewal, suggesting that ZEB1 as a potential therapeutic target for human gliomas with high PDGFRalpha activation.
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