Microvascular and Molecular Neuro-Oncology Laboratory, New York University School of Medicine, New York, NY 10016, USA.
J Neurooncol. 2010 Aug;99(1):33-40. doi: 10.1007/s11060-010-0111-2. Epub 2010 Feb 16.
Invasion is a hallmark of malignant gliomas and is the main reason for therapeutic failure and recurrence of the tumor. CXCR4 is a key chemokine receptor implicated in glioma cell migration whose expression is regulated by hypoxia. Here, we report that hepatocyte growth factor (HGF) upregulated CXCR4 protein expression in glioma cells. HGF pre-treatment increased migration of U87MG and LN229 glioma cells towards the CXCR4 ligand, stromal cell-derived factor-1alpha (SDF-1alpha). AMD3100, a CXCR4 inhibitor, inhibited the increased migration of HGF pre-treated LN229 glioma cells towards SDF-1alpha. Following exposure to HGF and hypoxia, both cell lines showed nuclear translocation of NF-kappaB (p65). The HGF- and hypoxia-induced nuclear translocation of NF-kappaB (p65) involved phosphorylation and degradation of IkappaB-alpha. Knock-down of NF-kappaB expression inhibited the induction of CXCR4 expression in response to HGF, but not to hypoxia. However, knock-down of NF-kappaB expression inhibited the induction of CXCR4 expression in response to hypoxia in the presence of HGF. NF-kappaB mediated migration towards SDF-1alpha in response to HGF. Knock-down of NF-kappaB expression resulted in decreased migration of HGF pre-treated glioma cells towards SDF-1alpha. Therefore, HGF upregulates CXCR4 expression via NF-kappaB and leads to enhanced migration. To our knowledge, this is the first report to show that a crosstalk mediated by NF-kappaB exists between the SDF-1alpha/CXCR4 and HGF/c-Met axes relevant to glioma cell migration. These findings imply that effective inhibition of glioma invasion should be directed against several ligand/receptor signaling pathways.
浸润是恶性神经胶质瘤的一个标志，也是治疗失败和肿瘤复发的主要原因。趋化因子受体 4（CXCR4）是一种关键的趋化因子受体，参与神经胶质瘤细胞的迁移，其表达受缺氧的调节。在这里，我们报告肝细胞生长因子（HGF）上调神经胶质瘤细胞中 CXCR4 蛋白的表达。HGF 预处理增加了 U87MG 和 LN229 神经胶质瘤细胞向 CXCR4 配体基质细胞衍生因子-1α（SDF-1α）的迁移。CXCR4 抑制剂 AMD3100 抑制了 HGF 预处理的 LN229 神经胶质瘤细胞向 SDF-1α 的迁移增加。暴露于 HGF 和缺氧后，两种细胞系均显示 NF-κB（p65）的核转位。HGF 和缺氧诱导的 NF-κB（p65）核转位涉及 IkappaB-α的磷酸化和降解。NF-κB 表达的敲低抑制了对 HGF 反应的 CXCR4 表达的诱导，但对缺氧无影响。然而，在存在 HGF 的情况下，NF-κB 表达的敲低抑制了对缺氧诱导的 CXCR4 表达的诱导。NF-κB 介导了对 HGF 反应的向 SDF-1α的迁移。NF-κB 表达的敲低导致 HGF 预处理的神经胶质瘤细胞向 SDF-1α的迁移减少。因此，HGF 通过 NF-κB 上调 CXCR4 表达，从而增强迁移。据我们所知，这是第一个报告显示，NF-κB 介导的 SDF-1α/CXCR4 和 HGF/c-Met 轴之间存在与神经胶质瘤细胞迁移相关的串扰。这些发现表明，有效的胶质瘤侵袭抑制应该针对几个配体/受体信号通路。
