Abstract：
Malignant peripheral nerve sheath tumors (MPNSTs) are an aggressive form of sarcomas with a poor prognosis and limited treatment options. Therefore, new therapeutic targets are urgently needed to identify novel drugs.
Based on the Gene Expression Omnibus database, an integrated analysis was performed to identify differentially expressed genes (DEGs) in MPNSTs compared to neurofibromas (NFs). Then functional enrichment analyses, protein-protein interaction (PPI) network construction, and hub gene selection were conducted. We explored DEG-guided repurposable drugs to treat MPNST based on the Library of Integrated Network-Based Cellular Signatures (LINCS) database. Furthermore, the binding affinity between predicted drug candidates and the MPNST-associated hub gene was calculated using molecular docking.
We identified 89 DEGs in common with all three MPNSTs datasets. In the PPI networks, twist family bHLH transcription factor 1 (Twist1) with higher node degrees was further evaluated as a therapeutic target. Cytochalasin-d, cabozantinib, everolimus, refametinib, and BGT-226 were extracted from the LINCS database, which showed lower normalized connectivity scores (-1.88, -1.81, -1.78, -1.76, and -1.72, respectively) and was considered as drug candidates. In addition, the results of molecular docking between the five drugs and Twist1 showed a binding affinity of -6.61, -7.03, -7.73, -3.94, and -7.07 kcal/mol, respectively.
Overall, our results describe the importance of Twist1 in MPNST pathogenesis. Everolimus was also found to be a potential therapeutic drug for MPNSTs.
Based on the Gene Expression Omnibus database, an integrated analysis was performed to identify differentially expressed genes (DEGs) in MPNSTs compared to neurofibromas (NFs). Then functional enrichment analyses, protein-protein interaction (PPI) network construction, and hub gene selection were conducted. We explored DEG-guided repurposable drugs to treat MPNST based on the Library of Integrated Network-Based Cellular Signatures (LINCS) database. Furthermore, the binding affinity between predicted drug candidates and the MPNST-associated hub gene was calculated using molecular docking.
We identified 89 DEGs in common with all three MPNSTs datasets. In the PPI networks, twist family bHLH transcription factor 1 (Twist1) with higher node degrees was further evaluated as a therapeutic target. Cytochalasin-d, cabozantinib, everolimus, refametinib, and BGT-226 were extracted from the LINCS database, which showed lower normalized connectivity scores (-1.88, -1.81, -1.78, -1.76, and -1.72, respectively) and was considered as drug candidates. In addition, the results of molecular docking between the five drugs and Twist1 showed a binding affinity of -6.61, -7.03, -7.73, -3.94, and -7.07 kcal/mol, respectively.
Overall, our results describe the importance of Twist1 in MPNST pathogenesis. Everolimus was also found to be a potential therapeutic drug for MPNSTs.
摘要：
背景：恶性外周神经鞘瘤（MPNSTs）是一种侵袭性肉瘤，预后差，治疗选择有限。因此,迫切需要新的治疗靶点来鉴定新药。
方法：基于基因表达综合数据库，我们进行了整合分析,以鉴定与神经纤维瘤(NFs)相比MPNSTs中差异表达的基因(DEG).然后进行功能富集分析，蛋白质-蛋白质相互作用(PPI)网络构建，并进行了hub基因选择。我们基于基于集成网络的细胞特征库（LINCS）数据库探索了DEG指导的可再利用药物来治疗MPNST。此外，使用分子对接计算预测的候选药物与MPNST相关hub基因之间的结合亲和力.
结果：我们确定了与所有三个MPNST数据集相同的89个DEG。在PPI网络中，具有较高节点度的twist家族bHLH转录因子1（Twist1）被进一步评估为治疗靶标。细胞松弛素-d,卡博替尼,依维莫司,refametinib,BGT-226是从LINCS数据库中提取的，显示较低的归一化连接评分(分别为-1.88,-1.81,-1.78,-1.76和-1.72),被认为是候选药物.此外,5种药物与Twist1的分子对接结果显示结合亲和力为-6.61,-7.03,-7.73,-3.94,-7.07kcal/mol,分别。
结论：总体而言，我们的结果描述了Twist1在MPNST发病机制中的重要性.依维莫司也被发现是MPNSTs的潜在治疗药物。
方法：基于基因表达综合数据库，我们进行了整合分析,以鉴定与神经纤维瘤(NFs)相比MPNSTs中差异表达的基因(DEG).然后进行功能富集分析，蛋白质-蛋白质相互作用(PPI)网络构建，并进行了hub基因选择。我们基于基于集成网络的细胞特征库（LINCS）数据库探索了DEG指导的可再利用药物来治疗MPNST。此外，使用分子对接计算预测的候选药物与MPNST相关hub基因之间的结合亲和力.
结果：我们确定了与所有三个MPNST数据集相同的89个DEG。在PPI网络中，具有较高节点度的twist家族bHLH转录因子1（Twist1）被进一步评估为治疗靶标。细胞松弛素-d,卡博替尼,依维莫司,refametinib,BGT-226是从LINCS数据库中提取的，显示较低的归一化连接评分(分别为-1.88,-1.81,-1.78,-1.76和-1.72),被认为是候选药物.此外,5种药物与Twist1的分子对接结果显示结合亲和力为-6.61,-7.03,-7.73,-3.94,-7.07kcal/mol,分别。
结论：总体而言，我们的结果描述了Twist1在MPNST发病机制中的重要性.依维莫司也被发现是MPNSTs的潜在治疗药物。
