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

• 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; 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

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.

神经纤维瘤病1型（NF1）是一种常染色体显性疾病，易于发展良性神经纤维瘤和恶性周围神经鞘瘤（MPNST）。 NF1相关的肿瘤发病机理的分子机制在很大程度上尚不清楚，并且尚未确定NF1肿瘤的医疗治疗策略。为了鉴定由NF1Gene缺乏介导的恶性肿瘤中的分子标记/靶标，我们在神经细胞ASA NF1疾病模型中建立了NF1基因敲低（KD）系统，并通过纳为蛋白质分析了基因/蛋白质的表达谱。在4000种非冗余蛋白半量化的蛋白中，我们提取了38个分子信号，否则在与对照细胞的NF1 kD细胞中进行了更新。这些蛋白主要与细胞运动，凋亡和细胞分化有关，包括几种新型蛋白质网络含神经元细胞，例如TCTP（翻译控制的肿瘤蛋白）-MTOR信号和Dynein-gr-cox1信号。我们证实，通过在响应生长因子中激活MAPK/PI3K-AKT信号，这些信号通过激活MAPK/PI3K-AKT信号显着上调了NF1缺陷神经细胞。这些信号的敲低或抑制剂处理抑制了NF1疾病模型/肿瘤细胞的可检测性和分化。这些结果表明，这些新型NF1相关的信号在功能上与肿瘤发生和进展有关，并作为NF1Tumors的诊断生物标志物/治疗靶标。