Open AccessEGR‐1 is Regulated by N‐Methyl‐D‐Aspartate‐Receptor Stimulation and Associated with Patient Survival in Human High Grade Astrocytomas
Author(s) -
Mittelbronn Michel,
Harter Patrick,
Warth Arne,
Lupescu Adrian,
Schilbach Karin,
Vollmann Henning,
Capper David,
Goeppert Benjamin,
Frei Karl,
Bertalanffy Helmut,
Weller Michael,
Meyermann Richard,
Lang Florian,
Simon Perikles
Publication year - 2009
Publication title -
brain pathology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.986
H-Index - 132
eISSN - 1750-3639
pISSN - 1015-6305
DOI - 10.1111/j.1750-3639.2008.00175.x
Subject(s) - astrocytoma , nmda receptor , cancer research , stimulation , biology , angiogenesis , glioma , receptor , neuroscience , biochemistry
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.