Wibowo Moh Arikus, Nugroho Eri Prasetyo, Hermawan Adam
Laboratory of Macromolecular Engineering, Department of Pharmaceutical Chemistry, Faculty of Pharmacy, Universitas Gadjah Mada Sekip Utara II, Yogyakarta, 55281, Indonesia.
Asian Pac J Cancer Prev. 2021 Dec 1;22(12):3949-3958. doi: 10.31557/APJCP.2021.22.12.3949.
Paeoniflorin (PF), a compound found in Paeonia lactiflora and Paeonia suffruticosa, has anticancer potential, particularly in inhibiting migration and invasion, the resistant cancer cells hallmarks. To date, the mechanism of overcoming tamoxifen resistance in breast cancer is not yet elucidated. This research aims to explore the potential target of PF as a co-treatment for circumventing breast cancer resistance to tamoxifen with a genomic understanding-bioinformatics.
Microarray data originating from GSE67916 and GSE85871 in the NCBI GEO database was analyzed to obtain differentially expressed genes (DEGs). Further analyses were performed on DEGs using the DAVID v6.8, STRING-DB v11.0, the Cytoscape, and cBioportal. Gene expression analysis validation in breast cancer cells and tamoxifen-resistant breast cancer cells was accomplished using GEPIA and ONCOMINE databases. Survival rate analysis of selected genes was conducted using Kaplan-Meier.
We obtained 175 DEGs from the two samples (tamoxifen-resistant and paeoniflorin-treated). DEG involves in 70 biological processes, 26 cellular components, and 18 molecular functions, and three pathways relevant to breast cancer. The PPI network analysis and hub genes selection obtained 10 genes with the highest degree scores. Genetic changes for selected genes, including IFNB1, CDK6, FGFR2, OAS1, BCL2, and STAT2 were found from 0.5% to 7% of the case population per patient case. Additional analysis using cBioportal revealed FGFR signaling pathway through Ras is important for the PF mechanism in circumventing breast cancer resistance to tamoxifen. ONCOMINE and GEPIA analysis emphasized the importance of selected genes in the tamoxifen-resistance mechanism.
PF has potential to be used as a co-treatment for circumventing breast cancer resistance to tamoxifen by targeting FGFR2 signaling, but further validation is needed.
芍药苷（PF）是一种存在于白芍和牡丹中的化合物，具有抗癌潜力，尤其在抑制迁移和侵袭方面，这是耐药癌细胞的特征。迄今为止，乳腺癌中克服他莫昔芬耐药性的机制尚未阐明。本研究旨在通过基因组理解——生物信息学探索PF作为联合治疗药物规避乳腺癌对他莫昔芬耐药的潜在靶点。
分析来自NCBI基因表达综合数据库（GEO）中GSE67916和GSE85871的微阵列数据，以获得差异表达基因（DEG）。使用DAVID v6.8、STRING-DB v11.0、Cytoscape和cBioportal对DEG进行进一步分析。利用GEPIA和ONCOMINE数据库完成乳腺癌细胞和他莫昔芬耐药乳腺癌细胞中的基因表达分析验证。使用Kaplan-Meier法对选定基因进行生存率分析。
我们从两个样本（他莫昔芬耐药样本和芍药苷处理样本）中获得了175个DEG。DEG涉及70个生物学过程、26个细胞成分和18个分子功能，以及三条与乳腺癌相关的通路。蛋白质-蛋白质相互作用（PPI）网络分析和枢纽基因选择获得了10个度值最高的基因。在每位患者病例的病例群体中，发现选定基因（包括IFNB1、CDK6、FGFR2、OAS1、BCL2和STAT2）的基因变化率为0.5%至7%。使用cBioportal进行的额外分析表明，通过Ras的FGFR信号通路对于PF规避乳腺癌对他莫昔芬耐药的机制很重要。ONCOMINE和GEPIA分析强调了选定基因在他莫昔芬耐药机制中的重要性。
PF有潜力通过靶向FGFR2信号通路作为联合治疗药物来规避乳腺癌对他莫昔芬的耐药性，但需要进一步验证。
