Ligand-dependent EphB1 signaling suppresses glioma invasion and correlates with patient survival
Ligand-dependent EphB1 signaling suppresses glioma invasion and correlates with patient survival
复制标题
配体依赖性 EphB1 信号传导抑制神经胶质瘤侵袭并与患者生存相关。
DOI：
10.1093/neuonc/not128
复制
发表时间：
2013-12-01
期刊：
影响因子：
15.9
通讯作者：
Hamada, Jun-Ichiro
中科院分区：
文献类型：
--
作者：
Teng, Lei;Nakada, Mitsutoshi;Hamada, Jun-Ichiro
背景
广泛的证据表明，Eph受体家族的酪氨酸激酶及其配体ePhin参与了胶质瘤的侵袭，但这些受体如何影响胶质瘤的趋化行为仍不完全清楚。我们试图确定与患者生存相关的Eph家族成员，并揭示Eph在胶质瘤侵袭中的作用。
方法
EphB基因的临床相关性在195例脑活检标本的临床注释表达数据集中得到证实。对EphB的体内外功能进行了分析。
结果
某些EphB成员的mRNA水平在胶质瘤的组织学分级中存在显著差异。根据Kaplan-Meier分析，尽管EphB1的表达水平在不同的肿瘤级别之间没有变化，但只有EphB的5个成员中的EphB1水平是恶性胶质瘤患者有利生存的有力预测因素(n=97，P=0.0048)。免疫沉淀结果显示，所有受试胶质瘤细胞均未检测到酪氨酸磷酸化的EphB1。在低表达细胞系(U251、U87)中，EphB1的强制过表达和自磷酸化不影响细胞的体外迁移和侵袭，而ePhin-B2/Fc诱导的EphB1的磷酸化显著降低了细胞的迁移和侵袭。表达EphB1的细胞表现出与迁移诱导相一致的显著的形态变化；这种变化被EphB1的过度表达所否定。同时，EphB1的过表达可抑制Ephin-B2在体内和体外诱导的迁移和侵袭的增加。
结论
这些数据表明，配体依赖的EphB1信号负向调节胶质瘤细胞的侵袭，表明EphB1是恶性胶质瘤的一个有利的预后因素。
BACKGROUND
Extensive evidence implicates the Eph receptor family of tyrosine kinases and its ligand, ephrin, in glioma invasion, but it remains incompletely understood how these receptors affect chemotactic behavior of glioma. We sought to identify the Eph family members that correlate with patients' survival and to reveal the function of Eph in glioma invasion.
METHODS
Clinical relevance of EphB genes was confirmed in a clinically annotated expression data set of 195 brain biopsy specimens. The function of EphB was analyzed in vitro and in vivo.
RESULTS
Levels of mRNA of certain EphB members were significantly different in histological grades of glioma. According to Kaplan-Meier analysis, only the EphB1 level among 5 members of EphB emerged to be a powerful predictor of favorable survival in malignant glioma (n = 97, P = .0048), although the levels of EphB1 expression did not vary across the tumor grades. Immunoprecipitation showed that tyrosine phosphorylated EphB1 was not detected in all glioma cells tested. Forced overexpression and autophosphorylation of EphB1 in low expressor cell lines (U251, U87) did not affect cell migration or invasion in vitro, whereas EphB1 phosphorylation induced by ephrin-B2/Fc significantly decreased migration and invasion. Cells expressing ephrin-B2 showed noteworthy morphological changes consistent with migration induction; this alteration was negated by EphB1 overexpression. Concomitantly, overexpression of EphB1 abrogated the increased migration and invasion induced by ephrin-B2 in vitro and in vivo.
CONCLUSIONS
These data suggest that ligand-dependent EphB1 signaling negatively regulates glioma cell invasion, identifying EphB1 as a favorable prognostic factor in malignant glioma.