Epidermal Growth Factor Receptor-Mediated Regulation of Urokinase Plasminogen Activator Expression and Glioblastoma Invasion via C-SRC/MAPK/AP-1 Signaling Pathways

• Published in: Journal of neuropathology and experimental neurology Vol. 69; no. 6; pp. 582 - 592
• Main Authors: Amos, Samson, Redpath, Gerard T, diPierro, Charles G, Carpenter, Joan E, Hussaini, Isa M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD American Association of Neuropathologists, Inc 01.06.2010; Lippincott Williams & Wilkins; Oxford University Press
• Subjects: Animals; Antineoplastic agents; Astrocytes - cytology; Astrocytes - drug effects; Astrocytes - metabolism; Biological and medical sciences; Blotting, Northern; Blotting, Western; Cell Line; Cell Movement - drug effects; Cells, Cultured; Chemotherapy; Epidermal Growth Factor - pharmacology; Glioblastoma - metabolism; Humans; Image Processing, Computer-Assisted; Magnetic Resonance Imaging; MAP Kinase Signaling System - drug effects; MAP Kinase Signaling System - physiology; Medical sciences; Mice; Neurology; Pharmacology. Drug treatments; Promoter Regions, Genetic - drug effects; Receptor, Epidermal Growth Factor - genetics; Receptor, Epidermal Growth Factor - metabolism; RNA, Messenger - genetics; RNA, Messenger - metabolism; RNA, Small Interfering; Time Factors; Transcription Factor AP-1 - genetics; Transcription Factor AP-1 - metabolism; Transfection; Transplantation, Heterologous; Urokinase-Type Plasminogen Activator - genetics; Urokinase-Type Plasminogen Activator - metabolism; Nervous system diseases; AP1 transcription factor; Enzyme; Transferases; Glioblastoma; Mitogen-activated protein kinase; Malignant tumor; Invasion; Epidermal growth factor receptor; Malignant glioma; Signal transduction; Urokinase; Growth factor receptor; Epidermal growth factor; C-Onc gene; Central nervous system disease; Signaling molecules; Cancer
• ISSN: 0022-3069; 1554-6578
• DOI: 10.1097/NEN.0b013e3181e008fe

One of the major pathophysiological features of malignant astrocytomas is their ability to infiltrate surrounding brain tissue. The epidermal growth factor receptor (EGFR) and proteases are known to be overexpressed in glioblastomas (GBMs), but the interaction between the activation of the EGFR and urokinase plasminogen activator (uPA) in promoting astrocytic tumor invasion has not been fully elucidated. Here, we characterized the signal transduction pathway(s) by which EGF regulates uPA expression and promotes astrocytoma invasion. We show that EGFR activation and constitutively active EGFR vIII in GBM cell lines upregulate uPA expression. Small-molecule inhibitors of mitogen-activated protein kinase, tyrosine kinase, and small interfering RNA targeting c-Src blocked uPA upregulation. Similarly, mutations in the activator protein 1 binding site of the uPA promoter reduced EGF-induced increases in uPA promoter activity. Treatment of GBM cells with EGF increased in vitro cell invasion, and the invasive phenotype was attenuated by gene silencing of uPA using small interfering RNA and short hairpin RNA. In addition, uPA knockdown clones formed smaller well-circumscribed tumors than nontarget U1242 control cells in a xenograft GBM mouse model in vivo. In summary, these results suggest that c-Src, mitogen-activated protein kinase, and a composite activator protein 1 on the uPA promoter are responsible for EGF-induced uPA expression and GBM invasion.