Study of the molecular mechanism of neural tumor formation mediatedby NF1 gene deficiency

NF1基因缺陷介导的神经肿瘤形成分子机制研究

基本信息

批准号：
22390281
负责人：
ARAKI Norie
金额：
$ 12.23万
依托单位：
Kumamoto University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2010
资助国家：
日本
起止时间：
2010 至 2012
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22390281/
关键词：
神経線維腫症 NF1 プロテオミクス腫瘍抑制シグナル Neurofibromin NF2 Merlin siRNA

项目摘要

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that predisposesindividuals to developing benign neurofibromas and malignant peripheral nerve sheathtumors (MPNSTs). The molecular mechanism of NF1-associated tumor pathogenesis has beenlargely unknown, and the strategy of medical treatments for NF1 tumors has not beenestablished. To identify the molecular marker/target in malignant tumors mediated by NF1gene deficiency, we established the NF1 gene knockdown (KD) system in neural cells asa NF1 disease model, and analyzed the expression profiles of genes/proteins by anintegrated proteomics. Of 4000 non-redundant proteins semi-quantitatively identified,we extracted 38 molecular signals which were abnormally upregulated in NF1 KD cellscompared with control cells. These proteins were mostly related to cell motility,apoptosis, and cell differentiation, and including several novel protein networks inneuronal cells, such as TCTP(Translationally Controlled Tumor Protein)-mTOR signal andDynein-GR-COX1 signal. We confirmed that these signals were significantly up-regulatedin NF1-deficient neural cells via the activation of MAPK/PI3K-AKT signaling in responseto growth factors. The knockdown or inhibitor treatments of these signals suppressed theviability and differentiation of NF1 disease model/tumor cells. These results suggestthat these novel NF1-related signals are functionally implicated in the tumorigenesisand it’s progression, and serves as a diagnostic biomarker/therapeutic target for NF1tumors.

1 型神经纤维瘤病 (NF1) 是一种常染色体显性遗传疾病，使个体易患良性神经纤维瘤和恶性周围神经鞘瘤 (MPNST)。 NF1 相关肿瘤发病机制的分子机制在很大程度上尚不清楚，并且 NF1 肿瘤的药物治疗策略尚不清楚。为了识别由 NF1 基因缺陷介导的恶性肿瘤的分子标记/靶标，我们建立了 NF1 基因敲低。我们将神经细胞中的KD系统作为NF1疾病模型，并通过综合蛋白质组学分析了半定量鉴定的4000个非冗余蛋白中的基因/蛋白质的表达谱，提取了与NF1 KD细胞相比异常上调的38个分子信号。这些蛋白质主要与细胞运动、细胞凋亡和细胞分化有关，包括神经元细胞中的一些新蛋白质网络，例如我们证实，通过响应生长因子激活 MAPK/PI3K-AKT 信号，TCTP（翻译控制肿瘤蛋白）-mTOR 信号和 Dynein-GR-COX1 信号在 NF1 缺陷的神经细胞中显着上调。这些信号的敲低或抑制剂治疗抑制了 NF1 疾病模型/肿瘤细胞的活力和分化。这些结果表明这些新的 NF1 相关信号在功能上与 NF1 相关。肿瘤发生及其进展，并作为 NF1 肿瘤的诊断生物标志物/治疗靶点。