Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Department of Gastroenterology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
Pathol Res Pract. 2021 Feb;218:153318. doi: 10.1016/j.prp.2020.153318. Epub 2020 Dec 13.
Dihydroartemisinin (DHA), an effective antimalarial drug, has been widely investigated as an anti-tumor agent. Although previous studies have indicated the potential therapeutic effects of DHA on multiple malignancies, its detailed molecular mechanisms in gastric cancer (GC) are still undocumented. In the present study, we applied network pharmacology and bioinformatics (gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses) to obtain the collective targets of DHA and GC and analyzed their involvement in constructing a protein-protein interaction (PPI) network. The top 10% hub targets in this network were identified, and TCGA database was utilized for the single gene analysis of their correlation with the prognosis of GC. CCK8, EdU, Transwell, and flow cytometry analyses were conducted, and subcutaneous xenograft tumor models were constructed to assess the effects of DHA on the tumorigenesis and invasion of GC. Furthermore, the targets of DHA were verified by molecular docking, quantitative real-time PCR (qPCR) and western blot analyses in GC cells. The results indicated that the common targets of DHA and GC were enriched in multiple cancer-related pathways including KDR, STAT1 and apoptosis signaling pathways, where the core genes included KDR, MMP9, STAT1, TP53, CASP3/7 and BCL2L1. The lowered expression of KDR and increased expression of TP53 and CASP7 harbored a favorable survival for patients with GC patients. CASP7 showed a positive correlation with CASP3 but a negative correlation with KDR and could be regarded as an independent protective factor for overall survival in GC. Moreover, DHA treatment induced cell apoptosis and suppressed the cell proliferation, DNA synthesis, cycle progression and invasive capabilities both in vitro and in vivo. DHA also upregulated p53, CASP3, and cleaved-CASP3 and downregulated BCL2L1, MMP9, KDR, p-KDR, STAT1 and p-STAT1 in GC cell lines. In conclusion, DHA could suppress the tumorigenesis and invasion of GC by regulating STAT1/KDR/MMP9 and p53/BCL2L1/CASP3/7 pathways. Our findings might provide a novel approach for the treatment of GC.
二氢青蒿素（DHA）是一种有效的抗疟药物，已被广泛研究作为一种抗肿瘤药物。虽然先前的研究表明 DHA 对多种恶性肿瘤具有潜在的治疗作用，但它在胃癌（GC）中的详细分子机制仍未被记录。在本研究中，我们应用网络药理学和生物信息学（基因本体论（GO）和京都基因与基因组百科全书（KEGG）分析）来获得 DHA 和 GC 的共同靶点，并分析它们在构建蛋白质-蛋白质相互作用（PPI）网络中的作用。确定了该网络中前 10%的枢纽靶点，并利用 TCGA 数据库对其与 GC 预后的相关性进行了单个基因分析。进行了 CCK8、EdU、Transwell 和流式细胞术分析，并构建了皮下移植瘤模型，以评估 DHA 对 GC 发生和侵袭的影响。此外，通过分子对接、定量实时 PCR（qPCR）和 Western blot 分析在 GC 细胞中验证了 DHA 的靶点。结果表明，DHA 和 GC 的共同靶点富集在包括 KDR、STAT1 和细胞凋亡信号通路在内的多种癌症相关途径中，核心基因包括 KDR、MMP9、STAT1、TP53、CASP3/7 和 BCL2L1。GC 患者中 KDR 表达降低和 TP53 和 CASP7 表达增加与患者的良好生存有关。CASP7 与 CASP3 呈正相关，与 KDR 呈负相关，可作为 GC 总生存期的独立保护因素。此外，DHA 治疗在体外和体内均诱导细胞凋亡并抑制细胞增殖、DNA 合成、周期进程和侵袭能力。DHA 还上调了 p53、CASP3 和 cleaved-CASP3，下调了 BCL2L1、MMP9、KDR、p-KDR、STAT1 和 p-STAT1 在 GC 细胞系中。总之，DHA 通过调节 STAT1/KDR/MMP9 和 p53/BCL2L1/CASP3/7 通路抑制 GC 的发生和侵袭。我们的研究结果可能为 GC 的治疗提供一种新方法。
