Qifan Zheng1, Lei Han1, Yucui Dong1, Jing Tian1, Wei Huang1, Zhaoyu Liu1, Xiuzhi Jia1, Tao Jiang1, Jianning Zhang1, Xia Li1, Chunsheng Kang1, Huan Ren1. 1. Department of Immunology, Harbin Medical University; Heilongjiang Provincial Key Laboratory for Infection and Immunity, Harbin, China (Q.-F.Z., Y.-C.D., J.T., W.H., Z.-Y.L., X.-Z.J., H.R.); Department of Neurosurgery, Beijing Tiantan Hospital, Capital Medical University, Beijing, China (T.J.); College of Bioinformatics, Harbin Medical University, Harbin, China (X.L.); Department of Neurosurgery, Tianjin Medical University General Hospital; Laboratory of Neuro-Oncology, Tianjin Neurological Institute; Key Laboratory of Post-trauma Neuro-repair and Regeneration in Central Nervous System, Ministry of Education; Tianjin Key Laboratory of Injuries, Variations and Regeneration of Nervous System, Tianjin, China (L.H., C.-S.K., J.-N.Z.); Chinese Glioma Cooperative Group (CGCG) (L.H., T.J., C.-S.K.).
Abstract
BACKGROUND: As a commonly mutated form of the epidermal growth factor receptor, EGFRvIII strongly promotes glioblastoma (GBM) tumor invasion and progression, but the mechanisms underlying this promotion are not fully understood. METHODS: Through gene manipulation, we established EGFRvIII-, wild-type EGFR-, and vector-expressing GBM cells. We used cDNA microarrays, bioinformatics analysis, target-blocking migration and invasion assays, Western blotting, and an orthotopic U87MG GBM model to examine the phenotypic shifts and treatment effects of EGFRvIII expression in vitro and in vivo. Confocal imaging, co-immunoprecipitation, and siRNA assays detected the focal adhesion-associated complex and their relationships to the EGFRvIII/JAK2/STAT3 axis in GBM cells. RESULTS: The activation of JAK2/STAT3 signaling is vital for promoting migration and invasion in EGFRvIII-GBM cells. AG490 or WP1066, the JAK2/STAT3 inhibitors, specifically destroyed EGFRvIII/JAK2/STAT3-related focal adhesions and depleted the activation of EGFR/Akt/FAK and JAK2/STAT3 signaling, thereby abolishing the ability of EGFRvIII-expressing GBM cells to migrate and invade. Furthermore, the RNAi silencing of JAK2 in EGFRvIII-expressing GBM cells significantly attenuated their ability to migrate and invade; however, as a result of a potential EGFRvIII-JAK2-STAT3 activation loop, neither EGFR nor STAT3 knockdown yielded the same effects. Moreover, AG490 or JAK2 gene knockdown greatly suppressed tumor invasion and progression in the U87MG-EGFRvIII orthotopic models. CONCLUSION: Taken together, our data demonstrate that JAK2/STAT3 signaling is essential for EGFRvIII-driven migration and invasion by promoting focal adhesion and stabilizing the EGFRvIII/JAK2/STAT3 axis. Targeting JAK2/STAT3 therapy, such as AG490, may have potential clinical implications for the tailored treatment of GBM patients bearing EGFRvIII-positive tumors.
BACKGROUND: As a commonly mutated form of the epidermal growth factor receptor, EGFRvIII strongly promotes glioblastoma (GBM) tumor invasion and progression, but the mechanisms underlying this promotion are not fully understood. METHODS: Through gene manipulation, we established EGFRvIII-, wild-type EGFR-, and vector-expressing GBM cells. We used cDNA microarrays, bioinformatics analysis, target-blocking migration and invasion assays, Western blotting, and an orthotopic U87MG GBM model to examine the phenotypic shifts and treatment effects of EGFRvIII expression in vitro and in vivo. Confocal imaging, co-immunoprecipitation, and siRNA assays detected the focal adhesion-associated complex and their relationships to the EGFRvIII/JAK2/STAT3 axis in GBM cells. RESULTS: The activation of JAK2/STAT3 signaling is vital for promoting migration and invasion in EGFRvIII-GBM cells. AG490 or WP1066, the JAK2/STAT3 inhibitors, specifically destroyed EGFRvIII/JAK2/STAT3-related focal adhesions and depleted the activation of EGFR/Akt/FAK and JAK2/STAT3 signaling, thereby abolishing the ability of EGFRvIII-expressing GBM cells to migrate and invade. Furthermore, the RNAi silencing of JAK2 in EGFRvIII-expressing GBM cells significantly attenuated their ability to migrate and invade; however, as a result of a potential EGFRvIII-JAK2-STAT3 activation loop, neither EGFR nor STAT3 knockdown yielded the same effects. Moreover, AG490 or JAK2 gene knockdown greatly suppressed tumor invasion and progression in the U87MG-EGFRvIII orthotopic models. CONCLUSION: Taken together, our data demonstrate that JAK2/STAT3 signaling is essential for EGFRvIII-driven migration and invasion by promoting focal adhesion and stabilizing the EGFRvIII/JAK2/STAT3 axis. Targeting JAK2/STAT3 therapy, such as AG490, may have potential clinical implications for the tailored treatment of GBM patients bearing EGFRvIII-positive tumors.
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