Autocrine semaphorin 3A signaling promotes glioblastoma dispersal
Autocrine semaphorin 3A signaling promotes glioblastoma dispersal
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DOI：
10.1038/onc.2009.204
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发表时间：
2009-10-08
期刊：
影响因子：
8
通讯作者：
Jay, D. G.
中科院分区：
文献类型：
--
作者：
Bagci, T.;Wu, J. K.;Jay, D. G.
多形性胶质母细胞瘤（GBM）是最恶性的胶质瘤类型，由于广泛的肿瘤细胞浸润而具有弥漫性边界。因此，了解GBM细胞分散的机制对于开发有效的治疗方法以限制浸润至关重要。我们通过功能性蛋白质组学筛选鉴定了神经纤毛蛋白-1作为癌细胞侵袭的介质，并显示了其在GBM细胞中的作用。神经纤毛蛋白-1是脑信号蛋白3A（Sema 3A）的受体，Sema 3A是一种分泌的化学排斥剂，在神经发育期间促进轴突引导。虽然神经纤毛蛋白-1在GBM中的表达以前被证明，但其作为Sema 3A受体的作用仍然难以捉摸。使用荧光团辅助的光灭活和RNA干扰，我们表明，神经纤毛蛋白-1是所需的GBM细胞迁移。我们还发现GBM细胞内源性分泌Sema 3A，RNA干扰介导的Sema 3A下调抑制了迁移并改变了依赖于Rac 1活性的细胞形态。Sema 3A耗竭也减少了扩散，这是通过外源供应Sema 3A恢复。Sema 3A的细胞外应用以神经纤毛蛋白-1依赖性方式降低细胞-基质粘附。使用免疫组化，我们发现，Sema 3A是过表达的一个子集的人GBM相比，非肿瘤性脑。总之，这些发现暗示Sema 3A作为神经纤毛蛋白-1的自分泌信号，通过调节底物粘附来促进GBM分散，并表明靶向Sema 3A-神经纤毛蛋白-1信号传导可能限制GBM浸润。Oncogene（2009）28，3537-3550; doi：10.1038/onc.2009.204; 2009年8月17日在线发表
Glioblastoma multiforme (GBM) is the most malignant glioma type with diffuse borders due to extensive tumor cell infiltration. Therefore, understanding the mechanism of GBM cell dispersal is critical for developing effective therapies to limit infiltration. We identified neuropilin-1 as a mediator of cancer cell invasion by a functional proteomic screen and showed its role in GBM cells. Neuropilin-1 is a receptor for semaphorin3A (Sema3A), a secreted chemo-repellent that facilitates axon guidance during neural development. Although neuropilin-1 expression in GBMs was previously shown, its role as a Sema3A receptor remained elusive. Using fluorophore-assisted light inactivation and RNA interference, we showed that neuropilin-1 is required for GBM cell migration. We also showed that GBM cells secrete Sema3A endogenously, and RNA interference-mediated downregulation of Sema3A inhibits migration and alters cell morphology that is dependent on Rac1 activity. Sema3A depletion also reduces dispersal, which is recovered by supplying Sema3A exogenously. Extracellular application of Sema3A decreases cell-substrate adhesion in a neuropilin-1-dependent manner. Using immunohistochemistry, we showed that Sema3A is overexpressed in a subset of human GBMs compared with the non-neoplastic brain. Together, these findings implicate Sema3A as an autocrine signal for neuropilin-1 to promote GBM dispersal by modulating substrate adhesion and suggest that targeting Sema3A-neuropilin-1 signaling may limit GBM infiltration. Oncogene (2009) 28, 3537-3550; doi: 10.1038/onc.2009.204; published online 17 August 2009