Li Junfeng, Bao Jingfei, Wu Lichao, Sun Tengfei, Zhao Junhui, Luo Fei, Tao Fangfang, Liu Wenhong
School of Basic Medical Sciences, Zhejiang Chinese Medical University, Hangzhou, Zhejiang, 310000, China
Curr Cancer Drug Targets. 2024 Aug 6. doi: 10.2174/0115680096313623240801070716.
BACKGROUND: Hispolon, a phenolic compound isolated from the medicinal yellow fungal mulberry, exhibits a strong anti-triple-negative breast cancer (TNBC) effect. However, the antitumor mechanisms of Hispolon have not been fully explored. OBJECTIVE: In this study, we systematically investigated the mechanism of Hispolon against TNBC based on bioinformatics and in vitro experiments. METHODS: The Hispolon-related targets were first collected from the SwissTarget database. Differential Expression Genes (DEG) were screened between TNBC and normal breast tissue using the Gene Expression Comprehensive (GEO) dataset. The overlapping targets between Hispolon and DEG were analyzed by plotting Venn maps. Protein-protein interaction (PPI) network was constructed to analyze the interactions among these targets. The focus was on mining the core targets of anti-TNBC effects of Hispolon via the Cytohubba and MCODE plugin of Cytoscape 3.7.2 software. We performed survival analysis on these core targets to screen the best-matched targets, including EGFR, KIT, and PLAU. This correlated strongly with our validation of Hispolon by molecular docking. In addition, Gene Ontology (GO) analysis and KEGG pathway analysis were performed using R software (ClusterProfiler package). Finally, in vitro experiments were performed to assess the accuracy of predicted target genes. RESULTS: The ADME results suggested that Hispolon has great potential to develop into a drug. Twenty overlapping targets were screened by matching the 107 targets of Hispolon to the 2,013 targets of TNBC DEG. Seven core targets of Hispolon against TNBC were initially identified, including EGFR, IGFBP3, MMP9, MMP2, MMP1, PLAU, and KIT. GO enrichment analysis demonstrated that the biological process of Hispolon acting on TNBC mainly involves lymphocyte activation in immune response and phosphatidylinositol-mediated signal-ing. Additionally, the relaxin signaling pathway, estrogen signaling pathway, proteoglycans in cancer, and others might be the key pathways of Hispolon against TNBC. Furthermore, Hispolon inhibited the proliferation of MDA-MB-231 cells in a concentration-dependent manner and regulated the RNA and protein expression of the core targets EGFR, PLAU, and KIT for the treatment of TNBC. CONCLUSION: In this study, the polygenic pharmacological mechanism of action of Hispolon against TNBC was explored through network pharmacology and in vitro experiments, provid-ing a new insight into the mechanism of TCM monomer against TNBC.
背景：白藜芦醇是从药用黄色真菌桑黄中分离出的一种酚类化合物，具有很强的抗三阴性乳腺癌（TNBC）作用。然而，白藜芦醇的抗肿瘤机制尚未得到充分探索。 目的：在本研究中，我们基于生物信息学和体外实验系统地研究了白藜芦醇抗TNBC的机制。 方法：首先从SwissTarget数据库收集与白藜芦醇相关的靶点。使用基因表达综合数据库（GEO）筛选TNBC与正常乳腺组织之间的差异表达基因（DEG）。通过绘制韦恩图分析白藜芦醇与DEG之间的重叠靶点。构建蛋白质-蛋白质相互作用（PPI）网络以分析这些靶点之间的相互作用。重点是通过Cytoscape 3.7.2软件的Cytohubba和MCODE插件挖掘白藜芦醇抗TNBC作用的核心靶点。我们对这些核心靶点进行生存分析以筛选最佳匹配靶点，包括表皮生长因子受体（EGFR）、干细胞生长因子受体（KIT）和纤溶酶原激活物（PLAU）。这与我们通过分子对接对白藜芦醇的验证密切相关。此外，使用R软件（ClusterProfiler包）进行基因本体（GO）分析和京都基因与基因组百科全书（KEGG）通路分析。最后，进行体外实验以评估预测靶基因的准确性。 结果：药物代谢动力学（ADME）结果表明白藜芦醇具有很大的开发成药物的潜力。通过将白藜芦醇的107个靶点与TNBC的DEG的2013个靶点进行匹配，筛选出20个重叠靶点。初步确定了白藜芦醇抗TNBC的7个核心靶点，包括EGFR、胰岛素样生长因子结合蛋白3（IGFBP3）、基质金属蛋白酶9（MMP9）、基质金属蛋白酶2（MMP2）、基质金属蛋白酶1（MMP1）、PLAU和KIT。GO富集分析表明，白藜芦醇作用于TNBC的生物学过程主要涉及免疫反应中的淋巴细胞活化和磷脂酰肌醇介导的信号传导。此外，松弛素信号通路、雌激素信号通路、癌症中的蛋白聚糖等可能是白藜芦醇抗TNBC的关键通路。此外，白藜芦醇以浓度依赖性方式抑制MDA-MB-231细胞的增殖，并调节用于治疗TNBC的核心靶点EGFR、PLAU和KIT的RNA和蛋白质表达。 结论：在本研究中，通过网络药理学和体外实验探索了白藜芦醇抗TNBC的多基因药理作用机制，为中药单体抗TNBC的机制提供了新的见解。
Drug Des Devel Ther. 2024-4-10
Front Biosci (Landmark Ed). 2023-12-26
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