Hermawan Adam, Putri Herwandhani, Hanif Naufa, Ikawati Muthi
Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta 55281, Indonesia.
Cancer Chemoprevention Research Center, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta 55281, Indonesia.
Evid Based Complement Alternat Med. 2021 Jul 13;2021:2234554. doi: 10.1155/2021/2234554. eCollection 2021.
Agents that target metastasis are important to improve treatment efficacy in patients with breast cancer. Tangeretin, a citrus flavonoid, exhibits antimetastatic effects on breast cancer cells, but its molecular mechanism remains unclear. Tangeretin targets were retrieved from PubChem, whereas metastatic breast cancer regulatory genes were downloaded from PubMed. In total, 58 genes were identified as potential therapeutic target genes of tangeretin (PTs). GO and KEGG pathway enrichment analyses of PTs were performed using WebGestalt (WEB-based Gene SeT AnaLysis Toolkit). The PPI network was analyzed using STRING-DB v11.0 and visualized by Cytoscape software. Hub genes were selected on the basis of the highest degree score as calculated by the CytoHubba plugin. Genetic alterations of the PTs were analyzed using cBioPortal. The prognostic values of the PTs were evaluated with the Kaplan-Meier plot. The expression of PTs across breast cancer samples was confirmed using GEPIA. The reliability of the PTs in metastatic breast cancer cells was validated using ONCOMINE. Molecular docking was performed to foresee the binding sites of tangeretin with PIK3C, MMP9, PTGS2, COX-2, and IKK. GO analysis showed that PTs participate in the biological process of stimulus response, are the cellular components of the nucleus and the membrane, and play molecular roles in enzyme regulation. KEGG pathway enrichment analysis revealed that PTs regulate the PI3K/Akt pathway. Genetic alterations for each target gene were (3%), (4%), (42%), (4%), (3%), (32%), (15%), and (5%). The Kaplan-Meier plot showed that patients with low mRNA expression levels of and and high expression of had a significantly better prognosis than their counterparts. Further validation of gene expression by using GEPIA revealed that the mRNA expression of was significantly higher in breast cancer tissues than in normal tissues, whereas the mRNA expression of showed the opposite. Analysis with ONCOMINE demonstrated that the mRNA expression levels of and were significantly higher in metastatic breast cancer cells than in normal tissues. The results of molecular docking analyses revealed the advantage of tangeretin as an inhibitor of PIK3CA, MMP9, PTGS2, and IKK. Tangeretin inhibits metastasis in breast cancer cells by targeting TP53, PTGS2, MMP9, and PIK3CA and regulating the PI3K/Akt signaling pathway. Further investigation is needed to validate the results of this study.
靶向转移的药物对于提高乳腺癌患者的治疗效果至关重要。橘皮素是一种柑橘类黄酮，对乳腺癌细胞具有抗转移作用，但其分子机制尚不清楚。从PubChem检索橘皮素的靶点，而转移性乳腺癌调控基因则从PubMed下载。总共鉴定出58个基因作为橘皮素的潜在治疗靶点基因（PTs）。使用WebGestalt（基于网络的基因集分析工具包）对PTs进行GO和KEGG通路富集分析。使用STRING-DB v11.0分析PPI网络，并通过Cytoscape软件进行可视化。根据CytoHubba插件计算的最高度得分选择枢纽基因。使用cBioPortal分析PTs的基因改变。用Kaplan-Meier图评估PTs的预后价值。使用GEPIA确认PTs在乳腺癌样本中的表达。使用ONCOMINE验证PTs在转移性乳腺癌细胞中的可靠性。进行分子对接以预测橘皮素与PIK3C、MMP9、PTGS2、COX-2和IKK的结合位点。GO分析表明，PTs参与刺激反应的生物学过程，是细胞核和细胞膜的细胞成分，并在酶调节中发挥分子作用。KEGG通路富集分析显示，PTs调节PI3K/Akt通路。每个靶基因的基因改变分别为（3%）、（4%）、（42%）、（4%）、（3%）、（32%）、（15%）和（5%）。Kaplan-Meier图显示，TP53和PTGS2 mRNA表达水平低且PIK3CA表达高的患者预后明显优于其对应患者。使用GEPIA进一步验证基因表达表明，PIK3CA在乳腺癌组织中的mRNA表达明显高于正常组织，而PTGS2的mRNA表达则相反。ONCOMINE分析表明，MMP9和TP53在转移性乳腺癌细胞中的mRNA表达水平明显高于正常组织。分子对接分析结果揭示了橘皮素作为PIK3CA、MMP9、PTGS2和IKK抑制剂的优势。橘皮素通过靶向TP53、PTGS2、MMP9和PIK3CA并调节PI3K/Akt信号通路来抑制乳腺癌细胞的转移。需要进一步研究来验证本研究的结果。
