EGR-1 is regulated by N-methyl-D-aspartate-receptor stimulation and associated with patient survival in human high grade astrocytomas

Brain Pathol. 2009 Apr;19(2):195-204. doi: 10.1111/j.1750-3639.2008.00175.x. Epub 2008 May 16.


Early growth response-1 (EGR-1) is considered a central regulator in tumor cell proliferation, migration and angiogenesis and a promising candidate for gene therapy in human astrocytomas. However, conflicting data have been reported suggesting that both tumor promoting and anti-tumor activity of EGR-1 and its regulation, expression and prognostic significance still remain enigmatic. Our study explored EGR-1 expression and regulation in astrocytomas and its association with patient survival. As we detected two EGR-1 mRNA variants, one containing a N-methyl-D-aspartate-receptor (NMDA-R) responsive cytoplasmic polyadenylation element (CPE), further experiments were performed to determine the functional role of this pathway. After NMDA stimulation of SV-FHAS and neoplastic astrocytes, real-time polymerase chain reaction showed an increase of the CPE, containing EGR-1 splice variant only in astrocytoma cells. The surface expression and functionality of NMDA-R were demonstrated by flow cytometric analysis and measurement of increased intracellular Ca(2+). EGR-1 was mainly restricted to tumor cells expressing NMDA-R and significantly up-regulated in astrocytic tumors compared with normal brain. Further, EGR-1 expression was significantly (P < 0.007) associated with enhanced patient survival and was an independent prognostic factor in multivariate analysis in high grade astrocytomas. The NMDA-R-mediated EGR-1 expression, therefore, seems to be a promising target for novel clinical approaches to astrocytoma treatment.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Astrocytoma / genetics
  • Astrocytoma / metabolism*
  • Astrocytoma / mortality*
  • Astrocytoma / pathology
  • Brain / metabolism
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / mortality
  • Brain Neoplasms / pathology
  • Calcium / metabolism
  • Cell Line, Tumor
  • Early Growth Response Protein 1 / genetics
  • Early Growth Response Protein 1 / metabolism*
  • Flow Cytometry
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic
  • Glioblastoma / metabolism
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Multivariate Analysis
  • N-Methylaspartate / metabolism
  • N-Methylaspartate / pharmacology
  • Polymerase Chain Reaction
  • Protein Isoforms
  • RNA, Messenger / metabolism
  • Receptors, N-Methyl-D-Aspartate / metabolism*
  • Tumor Cells, Cultured


  • EGR1 protein, human
  • Early Growth Response Protein 1
  • Protein Isoforms
  • RNA, Messenger
  • Receptors, N-Methyl-D-Aspartate
  • N-Methylaspartate
  • Calcium