title: Ligand-dependent EphB1 signaling suppresses glioma invasion and correlates with patient survival.
abstract: BACKGROUND
  Extensive evidence implicates the Eph receptor family of tyrosine kinases and its ligand, ephrin, in glioma invasion, but it remains incompletely understood how these receptors affect chemotactic behavior of glioma. We sought to identify the Eph family members that correlate with patients' survival and to reveal the function of Eph in glioma invasion.
  
  
  METHODS
  Clinical relevance of EphB genes was confirmed in a clinically annotated expression data set of 195 brain biopsy specimens. The function of EphB was analyzed in vitro and in vivo.
  
  
  RESULTS
  Levels of mRNA of certain EphB members were significantly different in histological grades of glioma. According to Kaplan-Meier analysis, only the EphB1 level among 5 members of EphB emerged to be a powerful predictor of favorable survival in malignant glioma (n = 97, P = .0048), although the levels of EphB1 expression did not vary across the tumor grades. Immunoprecipitation showed that tyrosine phosphorylated EphB1 was not detected in all glioma cells tested. Forced overexpression and autophosphorylation of EphB1 in low expressor cell lines (U251, U87) did not affect cell migration or invasion in vitro, whereas EphB1 phosphorylation induced by ephrin-B2/Fc significantly decreased migration and invasion. Cells expressing ephrin-B2 showed noteworthy morphological changes consistent with migration induction; this alteration was negated by EphB1 overexpression. Concomitantly, overexpression of EphB1 abrogated the increased migration and invasion induced by ephrin-B2 in vitro and in vivo.
  
  
  CONCLUSIONS
  These data suggest that ligand-dependent EphB1 signaling negatively regulates glioma cell invasion, identifying EphB1 as a favorable prognostic factor in malignant glioma.
authors.affiliation: Corresponding Authors: Mitsutoshi Nakada, MD, PhD, Department of Neurosurgery, Division of Neuroscience, Graduate School of Medical Science, Kanazawa University, 13-1 Takara-machi, Kanazawa, Ishikawa 920-8641, Japan. mnakada@med.kanazawa-u.ac.jp); Shi-Guang Zhao, MD, PhD, Department of Neurosurgery, The First Affiliated Hospital of Harbin Medical University, Harbin, People's Republic of China (guangsz@hotmail.com.
authors.forename: Lei
authors.initials: L
authors.lastname: Teng
authors.forename: Mitsutoshi
authors.initials: M
authors.lastname: Nakada
authors.forename: Natsuki
authors.initials: N
authors.lastname: Furuyama
authors.forename: Hemragul
authors.initials: H
authors.lastname: Sabit
authors.forename: Takuya
authors.initials: T
authors.lastname: Furuta
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Hayashi
authors.forename: Takahisa
authors.initials: T
authors.lastname: Takino
authors.forename: Yu
authors.initials: Y
authors.lastname: Dong
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sato
authors.forename: Yoshimichi
authors.initials: Y
authors.lastname: Sai
authors.forename: Ken-Ichi
authors.initials: K
authors.lastname: Miyamoto
authors.forename: Michael E
authors.initials: ME
authors.lastname: Berens
authors.forename: Shi-Guang
authors.initials: SG
authors.lastname: Zhao
authors.forename: Jun-Ichiro
authors.initials: J
authors.lastname: Hamada
mesh_terms: D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D002465:Cell Movement; D049109:Cell Proliferation; D036387:Ephrin-B1 / Q000235:genetics / Q000378:metabolism*; D036388:Ephrin-B2 / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D005910:Glioma / Q000378:metabolism / Q000401:mortality* / Q000473:pathology; D006801:Humans; D007124:Immunoenzyme Techniques; D047468:Immunoprecipitation; D008024:Ligands; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D060787:Neoplasm Grading; D009361:Neoplasm Invasiveness; D020411:Oligonucleotide Array Sequence Analysis; D010766:Phosphorylation; D011379:Prognosis; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D014408:Biomarkers, Tumor; D036387:Ephrin-B1; D036388:Ephrin-B2; D008024:Ligands; D012333:RNA, Messenger
keywords: Eph-ephrin; glioma; invasion; migration; tyrosine kinase