EGR-1 is regulated by N-methyl-D-aspartate-receptor stimulation and associated with patient survival in human high grade astrocytomas.
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.
Mittelbronn
Michel
M
Institute of Brain Research, University of Tübingen, Tübingen, Germany. mittelbronn@usz.ch
Harter
Patrick
P
Warth
Arne
A
Lupescu
Adrian
A
Schilbach
Karin
K
Vollmann
Henning
H
Capper
David
D
Goeppert
Benjamin
B
Frei
Karl
K
Bertalanffy
Helmut
H
Weller
Michael
M
Meyermann
Richard
R
Lang
Florian
F
Simon
Perikles
P
D001254:Astrocytoma / Q000235:genetics / Q000378:metabolism* / Q000401:mortality* / Q000473:pathology; D001921:Brain / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002118:Calcium / Q000378:metabolism; D045744:Cell Line, Tumor; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism*; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D053208:Kaplan-Meier Estimate; D015999:Multivariate Analysis; D016202:N-Methylaspartate / Q000378:metabolism / Q000494:pharmacology; D016133:Polymerase Chain Reaction; D020033:Protein Isoforms; D012333:RNA, Messenger / Q000378:metabolism; D016194:Receptors, N-Methyl-D-Aspartate / Q000378:metabolism*; D014407:Tumor Cells, Cultured
C497325:EGR1 protein, human; D051766:Early Growth Response Protein 1; D020033:Protein Isoforms; D012333:RNA, Messenger; D016194:Receptors, N-Methyl-D-Aspartate; D016202:N-Methylaspartate; D002118:Calcium