Guanylate binding protein-1 mediates EGFRvIII and promotes glioblastoma growth in vivo but not in vitro.

Qing Lan,Lili Sun,Lei Hong,Aidong Wang,Yanwei Cheng,Akitaki Mukasa,Shuye Yu,Qiang Huang,Benjamin Purow,Ming Li,Jiawei Ma

doi:10.18632/oncotarget.7109

Abstract

Glioblastoma multiforme (GBM) is the most common and deadly primary brain tumor in adults. Epidermal growth factor receptor (EGFR) is frequently amplified and mutated in GBM. We previously reported that Guanylate binding protein-1 (GBP1) is a novel transcriptional target gene of EGFR and plays a role in GBM invasion. Here we demonstrate that GBP1 can also be induced by EGFRvIII at the transcriptional level through the p38 MAPK/Yin Yang 1 (YY1) signaling pathway. Silencing of GBP1 by RNA interference significantly inhibits EGFRvIII-mediated GBM cell proliferation in vitro and in a mouse model. Overexpression of GBP1 has no obvious effect on glioblastoma cell proliferation in vitro. In contrast, in an orthotopic glioma mouse model GBP1 overexpression significantly promotes glioma growth and reduces survival rate of glioma-bearing mice by increasing cell proliferation and decreasing cell apoptosis in tumor. Clinically, GBP1 expression is elevated in human GBM tumors and positively correlates with EGFRvIII status in GBM specimens, and its expression is inversely correlated with the survival rate of GBM patients. Taken together, these results reveal that GBP1 may serve as a potential therapeutic target for GBMs with EGFRvIII mutation.

Highlights

Glioblastoma multiforme (GBM) is the most common and most malignant brain tumor, accounting for ~20% of all the intracranial tumors in adults
It was found that Guanylate binding protein-1 (GBP1) expression is significantly higher at both the messenger RNA (mRNA) and protein levels in EGFRvIII expressing cells as compared to the parental and DK cells (Figure 1A and 1B), suggesting Epidermal growth factor receptor (EGFR) activation is essential for GBP1 induction
To determine whether EGFRvIII–induced GBP1 expression was directly regulated at the transcriptional level, U87-EGFRvIII cells were treated with 5 μg/ml actinomycin D (AD; a transcription inhibitor) or 100 nM cycloheximide (CHX; a protein synthesis inhibitor) for 24 h prior to RNA collection

Summary

Introduction

Glioblastoma multiforme (GBM) is the most common and most malignant brain tumor, accounting for ~20% of all the intracranial tumors in adults. GBM is characterized by infiltrating growth, necrosis, robust angiogenesis, and marked genetic heterogeneity [1]. These features make complete surgical removal impossible. The most common genetic lesions associated with GBM are amplification/ overexpression and mutation of the epidermal growth factor receptor (EGFR) gene, which are present in 40-60% of GBMs. The most common mutant form of EGFR, EGFR variant vIII (EGFRvIII), is found at 20-30% frequency in GBM. It was determined that EGFR amplification and mutation is more common in the classical subtype of GBM [5]. Since EGFRvIII is rarely found in normal tissue, it is an ideal therapeutic target against GBM. Efforts at targeting the EGFRvIII using small molecule inhibitors or antibodies have shown disappointing efficacy in clinical trials for GBM [9]

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Conclusion