EGF stimulates glioblastoma metastasis by induction of matrix metalloproteinase-9 in an EGFR-dependent mechanism

// Xing-Chen Chen 1 , Xiang-Tai Wei 1 , Jun-Hong Guan 1 , Hong Shu 1 and Duo Chen 1 1 Department of Neurosurgery, Shengjing Hospital of China Medical University, Shenyang 110004, P. R. China Correspondence to: Duo Chen, email: chend@sj-hospital.org Keywords: glioblastoma, epithelial growth factor, epithelial growth factor receptor, signal transducer and activator of transcription 3/5, matrix metalloproteinase-9 Received: February 20, 2017      Accepted: June 30, 2017      Published: July 27, 2017 ABSTRACT Epidermal growth factor (EGF) and EGF receptor (EGFR) play prominent roles in the metastasis of glioblastoma (GBM). However, the molecular mechanisms for the function of EGF and EGFR in GBM metastasis have not been elucidated. Herein, we demonstrate that coactivation of EGF and EGFR drives tumor metastasis in a matrix metalloproteinase-9 (MMP-9)–dependent manner. Expression levels of EGF, EGFR, and MMP-9 were substantially upregulated in the GBM and edema zones of patients, compared with those of paired unaffected participants. Secretion of EGF and MMP-9 was reduced in the cerebrospinal fluid (CSF) after removing GBM for 2 weeks by operation. To the mechanism, MMP-9 was upregulated by activating EGF and EGFR via PI3K/AKT- and ERK1/2-dependent pathways. Moreover, signal transducer and activator of transcription (STAT) 3 and STAT5 mediated the activation of NF-κB by PI3K/AKT and ERK1/2 pathways. This resulted in transactivation of MMP-9 in GBM. Finally, MMP-9 induction facilitated abnormal proliferation, migration, and invasion of cells, which contributed to GBM metastasis.