Zhang Biyu, Liu Genyan, Wang Xin, Hu Xuelei
Key Laboratory of Green Chemical Engineering Process of Ministry of Education, Hubei Key Laboratory of Novel Reactor and Green Chemical Technology, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, China.
School of Medicine, Jiujiang University, Jiujiang, China.
Front Genet. 2022 Jul 6;13:914646. doi: 10.3389/fgene.2022.914646. eCollection 2022.
Head and neck squamous cell carcinoma (HNSCC) represents one of the most malignant and heterogeneous tumors, and the patients have low 5-year survival. Traditional Chinese medicine (TCM) has been demonstrated as an effective complementary and/or alternative therapy for advanced malignancies including HNSCC. It has been noted that several herbs that are used for preparing Yinchen Wuling San (YWLS) have anti-tumor activities, whereas their mechanisms of action remain elusive. In this study, network pharmacology and molecular docking studies were employed to explore the underlying mechanisms of action of YWLS against HNSCC. The 58 active ingredients from six herbs used for YWLS and their 506 potential targets were screened from the traditional Chinese medicine systems pharmacology database and analysis platform (TCMSP) and SwissTargetPrediction database. A total of 2,173 targets associated with HNSCC were mainly identified from the DisGeNET and GeneCards databases. An active components-targets-disease network was constructed in the Cytoscape. Top 20 hub targets, such as AKT1, EGFR, TNF, ESR1, SRC, HSP90AA1, MAPK3, ERBB2, and CCND1, were identified by a degree in the protein-protein interaction (PPI) network. Gene functional enrichment analysis showed that PI3K-AKT, MAPK, Ras, TNF, and EGFR were the main signaling pathways of YWLS in treating HNSCC. There were 48 intersected targets such as EGFR, AKT1, and TNF that were associated with patients' outcomes by the univariate Cox analysis, and most of them had increased expression in the tumor as compared to normal tissues. The area under curves of receiver operating characteristic indicated their diagnostic potential. Inhibition of these survival-related targets and/or combination with EGFR or AKT inhibitors were promising therapeutic options in HNSCC. The partial active components of YWLS exhibited good binding with the hub targets, and ADME analysis further evaluated the drug-likeness of the active components. These compounds and targets identified in this study might provide novel treatment strategies for HNSCC patients, and the subsequent work is essential to verify the underlying mechanisms of YWLS against HNSCC.
头颈部鳞状细胞癌（HNSCC）是最具恶性和异质性的肿瘤之一，患者的5年生存率较低。中医已被证明是包括HNSCC在内的晚期恶性肿瘤的一种有效补充和/或替代疗法。已经注意到，几种用于制备茵陈五苓散（YWLS）的草药具有抗肿瘤活性，但其作用机制仍不清楚。在本研究中，采用网络药理学和分子对接研究来探索YWLS抗HNSCC的潜在作用机制。从中药系统药理学数据库和分析平台（TCMSP）以及SwissTargetPrediction数据库中筛选出用于YWLS的六种草药中的58种活性成分及其506个潜在靶点。总共从DisGeNET和GeneCards数据库中主要鉴定出2173个与HNSCC相关的靶点。在Cytoscape中构建了一个活性成分-靶点-疾病网络。通过蛋白质-蛋白质相互作用（PPI）网络中的度数鉴定出前20个枢纽靶点，如AKT1、EGFR、TNF、ESR1、SRC、HSP90AA1、MAPK3、ERBB2和CCND1。基因功能富集分析表明，PI3K-AKT、MAPK、Ras、TNF和EGFR是YWLS治疗HNSCC的主要信号通路。通过单变量Cox分析，有48个交集靶点如EGFR、AKT1和TNF与患者的预后相关，与正常组织相比，它们中的大多数在肿瘤中表达增加。受试者工作特征曲线下面积表明了它们的诊断潜力。抑制这些与生存相关的靶点和/或与EGFR或AKT抑制剂联合使用是HNSCC中有前景的治疗选择。YWLS的部分活性成分与枢纽靶点表现出良好的结合，ADME分析进一步评估了活性成分的类药性。本研究中鉴定出的这些化合物和靶点可能为HNSCC患者提供新的治疗策略，后续工作对于验证YWLS抗HNSCC的潜在机制至关重要。
