Glypican-1 is frequently overexpressed in human gliomas and enhances FGF-2 signaling in glioma cells
Glypican-1 is frequently overexpressed in human gliomas and enhances FGF-2 signaling in glioma cells
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DOI：
10.2353/ajpath.2006.050800
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发表时间：
2006-06-01
影响因子：
6
通讯作者：
Friedl, Andreas
中科院分区：
文献类型：
--
作者：
Su, Gui;Meyer, Kristy;Friedl, Andreas
成纤维细胞生长因子 2 (FGF-2) 是一种神经胶质瘤生长的自分泌刺激剂，其信号传导由硫酸乙酰肝素蛋白聚糖 (HSPG) 通过与 FGF-2 和 FGF 受体 (FGFR) 的三元复合物进行调节。为了表征神经胶质瘤生长信号，我们检查了改变的 HSPG 是否会导致神经胶质瘤生长控制的丧失。在对五种人类神经胶质瘤细胞系的筛选中，U118 和 U251 细胞 HSPG 通过 FGFR1c 激活 FGF-2 信号传导。 U251 神经胶质瘤细胞与正常星形胶质细胞 HSPG 的直接比较表明，神经胶质瘤 HSPG 通过 FGFR1c 促进 FGF-2 依赖性有丝分裂信号传导的能力显着升高。这种增强的活性与较高水平的总体硫酸化相关，特别是含有 2S 和 6S 的二糖的丰度。神经胶质瘤细胞表面 HSPG glypican-1 的表达与 FGF-2 共激活剂活性密切相关。此外，在（磷脂酰肌醇蛋白聚糖1缺陷的）U87神经胶质瘤细胞中强制表达磷脂酰肌醇蛋白聚糖1可增强其FGF-2反应。免疫组织化学分析显示，与非肿瘤性神经胶质增生相比，人星形细胞瘤和少突胶质细胞瘤样本中磷脂酰肌醇蛋白聚糖-1 高度显着过度表达。总之，这些观察结果表明，改变的 HSPG 有助于神经胶质瘤中通过 FGFR1c 增强 FGF-2 信号传导，而磷脂酰肌醇蛋白聚糖 (glypican-1) 在此有丝分裂途径中发挥重要作用。
Signaling by fibroblast growth factor 2 (FGF-2), an autocrine stimulator of glioma growth, is regulated by heparan sulfate proteoglycans (HSPGs) via a ternary complex with FGF-2 and the FGF receptor (FGFR). To characterize glioma growth signaling, we examined whether altered HSPGs contribute to loss of growth control in gliomas. In a screen of five human glioma cell lines, U118 and U251 cell HSPGs activated FGF-2 signaling via FGFR1c. The direct comparison of U251 glioma cells with normal astrocyte HSPGs demonstrated that the glioma HSPGs had a significantly elevated ability to promote FGF-2-dependent mitogenic signaling via FGFR1c. This enhanced activity correlated with a higher level of overall sulfation, specifically the abundance of 2S- and 6S-containing disaccharides. Glioma cell expression of the cell-surface HSPG glypican-1 closely mirrored the FGF-2 coactivator activity. Furthermore, forced expression of glypican-1 in (glypican-1-deficient) U87 glioma cells enhanced their FGF-2 response. Immunohistochemical analysis revealed a highly significant overexpression of glypican-1 in human astrocytoma and oligodendroglioma samples compared with non-neoplastic gliosis. In summary, these observations suggest that altered HSPGs contribute to enhanced signaling of FGF-2 via FGFR1c in gliomas with glypican-1 playing a significant role in this mitogenic pathway.