Overexpression of CD97 Confers an Invasive Phenotype in Glioblastoma Cells and Is Associated with Decreased Survival of Glioblastoma Patients

Michael Safaee,Gurvinder Kaur,Andrew T Parsa,Matthew Z Sun,Taemin Oh,Mitchel S Berger,Michael E Ivan,Aaron J Clark,Joseph M Kim,Orin Bloch,Michael C Oh,Roger Chammas

doi:10.1371/journal.pone.0062765

Michael Safaee, Gurvinder Kaur + Show 10 more

Open Access

https://doi.org/10.1371/journal.pone.0062765

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Abstract

Mechanisms of invasion in glioblastoma (GBM) relate to differential expression of proteins conferring increased motility and penetration of the extracellular matrix. CD97 is a member of the epidermal growth factor seven-span transmembrane family of adhesion G-protein coupled receptors. These proteins facilitate mobility of leukocytes into tissue. In this study we show that CD97 is expressed in glioma, has functional effects on invasion, and is associated with poor overall survival. Glioma cell lines and low passage primary cultures were analyzed. Functional significance was assessed by transient knockdown using siRNA targeting CD97 or a non-target control sequence. Invasion was assessed 48 hours after siRNA-mediated knockdown using a Matrigel-coated invasion chamber. Migration was quantified using a scratch assay over 12 hours. Proliferation was measured 24 and 48 hours after confirmed protein knockdown. GBM cell lines and primary cultures were found to express CD97. Knockdown of CD97 decreased invasion and migration in GBM cell lines, with no difference in proliferation. Gene-expression based Kaplan-Meier analysis was performed using The Cancer Genome Atlas, demonstrating an inverse relationship between CD97 expression and survival. GBMs expressing high levels of CD97 were associated with decreased survival compared to those with low CD97 (p = 0.007). CD97 promotes invasion and migration in GBM, but has no effect on tumor proliferation. This phenotype may explain the discrepancy in survival between high and low CD97-expressing tumors. This data provides impetus for further studies to determine its viability as a therapeutic target in the treatment of GBM.

Highlights

Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median survival of less than two years [1,2]
CD97 is Expressed in Primary Glioblastoma Cultures and Glioblastoma Cell Lines
Given a single report demonstrating CD97 in three GBM cell lines, we sought to determine if the receptor is expressed in human GBM tissue

Summary

Introduction

Glioblastoma (GBM) is the most common and aggressive primary brain tumor with a median survival of less than two years [1,2]. The invasive nature of gliomas is a major factor limiting complete removal despite aggressive surgical resection. Intracranial dissemination, either at diagnosis or progression, is a poor prognostic factor associated with decreased survival [3]. The mechanisms underlying GBM invasion remain to be fully elucidated. As our ability to characterize the molecular signatures of GBM improves, there is a growing need to identify markers that can predict aggressiveness and promote the development of targeted therapies. Since invasive tumors are known to confer a worse prognosis, there is a particular need to identify mediators of tumor invasion

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