CRMP5 Controls Glioblastoma Cell Proliferation and Survival through Notch-Dependent Signaling
CRMP5 Controls Glioblastoma Cell Proliferation and Survival through Notch-Dependent Signaling
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DOI：
10.1158/0008-5472.can-14-0631
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发表时间：
2015-09-01
期刊：
影响因子：
11.2
通讯作者：
Thomasset, Nicole
中科院分区：
文献类型：
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作者：
Moutal, Aubin;Honnorat, Jerome;Thomasset, Nicole
Collapsin response mediator protein 5（CRMP 5）是一个在神经系统发育中起重要作用的5种胞质蛋白家族。这种蛋白质首次在癌症诱导的自身免疫过程中被描述，导致神经退行性疾病（副肿瘤神经综合征）。CRMP 5表达已被报道作为高级别肺神经内分泌癌的生物标志物;然而，其功能作用尚未在任何癌症病理生理学背景下进行研究。在这项研究中，我们报告了在人类胶质母细胞瘤（GBM）活检中观察到的两种不同的CRMP 5表达模式，这些模式建立了CRMP 5表达、Notch受体信号传导和GBM细胞增殖之间的联系。我们证明，CRMP 5升高促进Notch受体表达和Akt激活在人类肿瘤细胞系，GBM干细胞，和原发性肿瘤活检。我们已经证明，CRMP 5和Notch在GBM异种移植物中的高表达与干细胞有关。这表明GBM活检中的高CRMP 5表达模式包括干细胞的子集。从机制上讲，CRMP 5通过劫持Notch受体来发挥作用，使其免于瘙痒依赖性溶酶体降解。我们的研究结果表明，CRMP 5通过控制Notch受体的降解，作为Notch信号传导和Akt激活的主要介体，这对定义GBM中与患者生存相关并可预测患者生存的生物标志物特征具有意义。（C）2015年AACR。
Collapsin response mediator protein 5 (CRMP5) belongs to a family of five cytosolic proteins that play a major role in nervous system development. This protein was first described in cancer-induced autoimmune processes, causing neurodegenerative disorders (paraneoplastic neurologic syndromes). CRMP5 expression has been reported to serve as a biomarker for high-grade lung neuroendocrine carcinomas; however, its functional roles have not been examined in any setting of cancer pathophysiology. In this study, we report two different CRMP5 expression patterns observed in human glioblastoma (GBM) biopsies that establish connections between CRMP5 expression, Notch receptor signaling, and GBM cell proliferation. We demonstrated that elevated CRMP5 promotes Notch receptor expression and Akt activation in human tumor cell lines, GBM stem cells, and primary tumor biopsies. We have shown that the high CRMP5 and Notch expression in GBM xenograft is related to stem cells. This suggests that high CRMP5 expression pattern in GBM biopsies encompasses a subset of stem cells. Mechanistically, CRMP5 functioned by hijacking Notch receptors from Itch-dependent lysosomal degradation. Our findings suggest that CRMP5 serves as a major mediator of Notch signaling and Akt activation by controlling the degradation of the Notch receptor, with implications for defining a biomarker signature in GBM that correlates with and may predict patient survival. (C)2015 AACR.