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

1型神经纤维瘤病（NF1）是一种常染色体显性遗传病，使个体易患良性神经纤维瘤和恶性周围神经鞘瘤（MPNSTs）。NF1相关肿瘤发病的分子机制在很大程度上是未知的，NF1肿瘤的药物治疗策略尚未建立。为了确定NF1基因缺失介导的恶性肿瘤分子标记/靶点，我们在神经细胞中建立了NF1基因敲低（KD）系统作为NF1疾病模型，并利用整合蛋白质组学分析了基因/蛋白的表达谱。在4000个半定量鉴定的非冗余蛋白中，我们提取了38个在NF1 KD细胞中与对照细胞相比异常上调的分子信号。这些蛋白主要与细胞运动、细胞凋亡和细胞分化有关，包括一些新颖的神经元蛋白网络，如TCTP(transltranslcontrolled Tumor protein)-mTOR信号和dynein - gr - cox1信号。我们证实这些信号在nf1缺失的神经细胞中通过激活MAPK/PI3K-AKT信号响应生长因子而显著上调。这些信号的敲除或抑制治疗抑制了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肿瘤的发生和进展有关，并可作为nf1肿瘤的诊断生物标志物/治疗靶点。

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.