title: Epidermal growth factor module-containing mucin-like receptor 2 is a newly identified adhesion G protein-coupled receptor associated with poor overall survival and an invasive phenotype in glioblastoma.
abstract: Epidermal growth factor (EGF) module-containing mucin-like receptor 2 (EMR2) is a member of the seven span transmembrane (TM7) adhesion G-protein coupled receptor subclass. It is abundantly expressed in immune cells of myeloid origin and appears to mediate cellular adhesion, migration, and signaling. Based on an analysis showing earlier mortality among glioblastoma patients whose tumors highly express EMR2, we studied its expression patterns in glioblastoma and potential to mediate cellular proliferation and invasion. We performed univariate analysis of overall survival in GBM patients expressing low, moderate, and high amounts of EMR2 based on publicly available microarray data in the Cancer Genome Atlas (TCGA). Using RT-PCR and western blotting, we studied mRNA and protein expression patterns of EMR2, respectively. We then employed siRNA knockdown of EMR2 in two human glioblastoma cell lines expressing high levels of EMR2 to assess functional effects on cellular proliferation and invasion, in vitro. Kaplan-Meier analysis of TCGA survival data for GBM demonstrated that EMR2 levels are inversely correlated with overall time until mortality (log rank, P < 0.01). EMR2 mRNA and protein is variably expressed in primary glioblastoma samples and human glioblastoma cell lines. When comparing cells transfected with siRNA targeting EMR2 to those transfected with a negative, scramble control, there was no difference in proliferation over 72 h in the SF767 and G55 glioblastoma cell lines. However, EMR2 knockout cells demonstrated an almost 3-fold reduction in migration compared to their negative controls (P < 0.05) in the SF767 cell line, and an almost 2-fold reduction (P < 0.05) in migration in the G55 cell line. We provide evidence that EMR2 is expressed in glioblastoma and has significant functional consequences on cellular invasion, but not proliferation. In light of its ability to promote adhesion and migration in immune cells, our data suggest that EMR2 may mediate similar phenomena in glioblastoma. The invasive phenotype conferred by EMR2 correlates with clinical data demonstrating poor survival in glioblastoma patients who express high levels of EMR2 in their tumor.
authors.affiliation: Brain Tumor Research Center, Department of Neurological Surgery, University of California, 505 Parnassus Ave, San Francisco, CA 94143, USA.
authors.forename: Martin J
authors.initials: MJ
authors.lastname: Rutkowski
authors.forename: Michael E
authors.initials: ME
authors.lastname: Sughrue
authors.forename: Ari J
authors.initials: AJ
authors.lastname: Kane
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Kim
authors.forename: Orin
authors.initials: O
authors.lastname: Bloch
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Parsa
mesh_terms: D015153:Blotting, Western; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*; D002448:Cell Adhesion; D002465:Cell Movement; D049109:Cell Proliferation; D005909:Glioblastoma / Q000378:metabolism / Q000401:mortality* / Q000473:pathology*; D006801:Humans; D009361:Neoplasm Invasiveness; D010641:Phenotype; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D043562:Receptors, G-Protein-Coupled / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
chemical_list: C412456:ADGRE2 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D043562:Receptors, G-Protein-Coupled