Pancreatic endoplasmic reticulum kinase activation promotes medulloblastoma cell migration and invasion through induction of vascular endothelial growth factor A.
Pancreatic endoplasmic reticulum kinase activation promotes medulloblastoma cell migration and invasion through induction of vascular endothelial growth factor A.
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DOI：
10.1371/journal.pone.0120252
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Lin W
中科院分区：
文献类型：
--
作者：
Jamison S;Lin Y;Lin W
越来越多的证据表明，内质网(ER)应激激活的胰腺内质网激酶(PERK)可使肿瘤细胞适应肿瘤微环境，并通过诱导血管内皮生长因子A(VEGF-A)促进肿瘤血管生成。最近的研究表明，血管内皮生长因子-A可以通过与血管内皮生长因子受体2(VEGFR2)结合，以自分泌的方式直接作用于某些类型的肿瘤细胞，从而促进肿瘤细胞的迁移和侵袭。尽管一些报道表明PERK的激活增加了髓母细胞瘤中VEGF-A的表达，但PERK或VEGF-A在髓母细胞瘤中所起的作用仍然不清楚。在这项研究中，我们用遗传学方法和药理学方法模拟了肿瘤患者中观察到的PERK活性的适度增强，发现适度激活的PERK信号促进了髓母细胞瘤细胞的迁移和侵袭，并增加了VEGF-A的产生。此外，使用VEGFR2抑制剂SU5416和VEGF-A中和抗体阻断VEGF-A/VEGFR2信号通路，我们的结果表明，肿瘤细胞来源的VEGF-A通过VEGFR2信号通路促进髓母细胞瘤细胞的迁移和侵袭，PERK激活对髓母细胞瘤细胞迁移和侵袭的促进作用需要VEGF-A和VEGFR2。因此，这些发现表明，适度的PERK激活通过增强VEGF-A/VEGFR2信号通路促进髓母细胞瘤细胞的迁移和侵袭。
Evidence is accumulating that activation of the pancreatic endoplasmic reticulum kinase (PERK) in response to endoplasmic reticulum (ER) stress adapts tumor cells to the tumor microenvironment and enhances tumor angiogenesis by inducing vascular endothelial growth factor A (VEGF-A). Recent studies suggest that VEGF-A can act directly on certain tumor cell types in an autocrine manner, via binding to VEGF receptor 2 (VEGFR2), to promote tumor cell migration and invasion. Although several reports show that PERK activation increases VEGF-A expression in medulloblastoma, the most common solid malignancy of childhood, the role that either PERK or VEGF-A plays in medulloblastoma remains elusive. In this study, we mimicked the moderate enhancement of PERK activity observed in tumor patients using a genetic approach and a pharmacologic approach, and found that moderate activation of PERK signaling facilitated medulloblastoma cell migration and invasion and increased the production of VEGF-A. Moreover, using the VEGFR2 inhibitor SU5416 and the VEGF-A neutralizing antibody to block VEGF-A/VEGFR2 signaling, our results suggested that tumor cell-derived VEGF-A promoted medulloblastoma cell migration and invasion through VEGFR2 signaling, and that both VEGF-A and VEGFR2 were required for the promoting effects of PERK activation on medulloblastoma cell migration and invasion. Thus, these findings suggest that moderate PERK activation promotes medulloblastoma cell migration and invasion through enhancement of VEGF-A/VEGFR2 signaling.
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