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
Institute of Brain Research, University of Tübingen, Tübingen, Germany.
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.
早期生长反应因子-1（EGR-1）被认为是肿瘤细胞增殖、迁移和血管生成的核心调节因子，也是人类星形细胞瘤基因治疗的一个有前景的候选因子。然而，已有相互矛盾的数据报道，提示EGR-1的促肿瘤和抗肿瘤活性及其调控、表达和预后意义仍不明确。我们的研究探讨了EGR-1在星形细胞瘤中的表达、调控及其与患者生存的关系。由于我们检测到两种EGR-1 mRNA变体，其中一种含有N-甲基-D-天冬氨酸受体（NMDA-R）反应性胞质聚腺苷酸化元件（CPE），因此进行了进一步实验以确定该途径的功能作用。在对SV-FHAS和肿瘤性星形胶质细胞进行NMDA刺激后，实时聚合酶链反应显示仅在星形细胞瘤细胞中含有CPE的EGR-1剪接变体增加。通过流式细胞术分析和细胞内Ca(2+)增加的测量证明了NMDA-R的表面表达和功能。EGR-1主要局限于表达NMDA-R的肿瘤细胞，与正常脑相比，在星形细胞肿瘤中显著上调。此外，EGR-1表达与患者生存期延长显著相关（P < 0.007），并且是高级别星形细胞瘤多因素分析中的独立预后因素。因此，NMDA-R介导的EGR-1表达似乎是星形细胞瘤治疗新临床方法的一个有前景的靶点。
