Knockdown of EphB1 receptor decreases medulloblastoma cell growth and migration and increases cellular radiosensitization.
Knockdown of EphB1 receptor decreases medulloblastoma cell growth and migration and increases cellular radiosensitization.
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DOI：
10.18632/oncotarget.3369
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发表时间：
2015-04-20
期刊：
影响因子：
--
通讯作者：
Karam SD
中科院分区：
文献类型：
--
作者：
Bhatia S;Baig NA;Timofeeva O;Pasquale EB;Hirsch K;MacDonald TJ;Dritschilo A;Lee YC;Henkemeyer M;Rood B;Jung M;Wang XJ;Kool M;Rodriguez O;Albanese C;Karam SD
Eph受体酪氨酸激酶家族成员及其肝配蛋白配体的表达在髓母细胞瘤中经常失调。我们评估了EphB 1在髓母细胞瘤细胞系和工程小鼠模型中的表达和功能作用。mRNA和蛋白表达谱显示EphB 1受体在人髓母细胞瘤细胞系DAOY和UW 228中表达。EphB 1的下调降低了细胞的生长和活力，降低了重要的细胞周期调节因子的表达，并增加了细胞周期G1期的细胞百分比。它还调节增殖和细胞存活标记物的表达。此外，DAOY细胞中EphB 1敲低导致迁移显著减少，这与β1-整联蛋白表达和磷酸化Src水平降低相关。此外，EphB 1敲低增强了培养物和基因工程小鼠髓母细胞瘤模型中髓母细胞瘤细胞的细胞放射敏感性。使用基因工程小鼠模型，我们建立了EphB 1的遗传丢失导致辐射后肿瘤复发的显着延迟与EphB 1表达对照肿瘤相比。综上所述，我们的研究结果证实EphB 1在髓母细胞瘤细胞生长、活力、迁移和辐射敏感性中起关键作用，使EphB 1成为一个有希望的治疗靶点。
The expression of members of the Eph family of receptor tyrosine kinases and their ephrin ligands is frequently dysregulated in medulloblastomas. We assessed the expression and functional role of EphB1 in medulloblastoma cell lines and engineered mouse models. mRNA and protein expression profiling showed expression of EphB1 receptor in the human medulloblastoma cell lines DAOY and UW228. EphB1 downregulation reduced cell growth and viability, decreased the expression of important cell cycle regulators, and increased the percentage of cells in G1 phase of the cell cycle. It also modulated the expression of proliferation, and cell survival markers. In addition, EphB1 knockdown in DAOY cells resulted in significant decrease in migration, which correlated with decreased β1-integrin expression and levels of phosphorylated Src. Furthermore, EphB1 knockdown enhanced cellular radiosensitization of medulloblastoma cells in culture and in a genetically engineered mouse medulloblastoma model. Using genetically engineered mouse models, we established that genetic loss of EphB1 resulted in a significant delay in tumor recurrence following irradiation compared to EphB1-expressing control tumors. Taken together, our findings establish that EphB1 plays a key role in medulloblastoma cell growth, viability, migration, and radiation sensitivity, making EphB1 a promising therapeutic target.
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