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

Xing-Chen Chen,Duo Chen,Jun-Hong Guan,Hong Shu,Xiang-Tai Wei

doi:10.18632/oncotarget.19622

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.

Highlights

Glioblastoma (GBM) is the most common primary brain tumor in adults and poses the highest risk of death of all human malignancies [1]
We found that expression levels of Epidermal growth factor (EGF), EGF receptor (EGFR), and matrix metalloproteinase-9 (MMP-9) were elevated during the course of GBM progression, but www.impactjournals.com/oncotarget were downregulated 2 weeks postoperatively, especially in the cerebrospinal fluid (CSF)
MMP-9 upregulation has been detected in GBMs, [16] and MMP-9 is involved in GBM metastasis [19]

Summary

Introduction

Glioblastoma (GBM) is the most common primary brain tumor in adults and poses the highest risk of death of all human malignancies [1]. During metastasis of GBM, the signals of epithelial growth factor (EGF) are amplified by the EGF receptor (EGFR) to promote tumor growth and survival [2]. EGFRvIII is correlated with ligand-independent and constitutive phosphorylation of the receptor [3, 4]. Tyrosine kinase activity is relatively low for EGFRvIII, [5] this activity is sufficient to hinder interactions with Casitas B-lineage proteins and impede the degradation of EGFR [6]. Detection of the variant length of the receptor is associated with a worse prognosis for glioma patients [7, 8]. The results of a clinical trial of glioma patients [9] confirmed the efficacy of a treatment in which the expression of EGFRvIII was decreased

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Results

Conclusion