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邓显光,刘丽芳,袁博.基于miRNA-mRNA探讨西黄丸干预乳腺癌骨转移的分子机制及预后分析[J].湖南中医药大学学报英文版,2022,42(12):2043-2051.[Click to copy
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| 基于miRNA-mRNA探讨西黄丸干预乳腺癌骨转移的分子机制及预后分析 |
| 邓显光,刘丽芳,袁博 |
| (湖南中医药大学第一附属医院乳腺科, 湖南 长沙 410007) |
| 摘要: |
| 目的 基于miRNA-mRNA互作模式,明晰西黄丸干预乳腺癌骨转移的分子机制并进行预后分析,为乳腺癌骨转移的药物干预靶点及生物标志物的确定提供理论依据。方法 综合GEO、TCGA、TargetScan、GeneCards、OMIM、TCMSP、STRING、HPA数据库,采用R语言及Cytoscape软件对西黄丸干预乳腺癌骨转移的分子靶点进行miRNA-mRNA互作关系构建;蛋白质-蛋白质相互作用(protein-protein interaction, PPI)及Hub基因拓扑分析;基因本体论(gene ontology, GO)和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes, KEGG)富集分析。进一步使用TCGA数据库,分析肿瘤组织与正常组织分子靶点的差异表达,并通过HPA数据库进行免疫组化结果的相互佐证。最后结合患者临床信息,分析Lasso回归后分子靶点的预后相关性,单因素Cox回归分析临床信息与分子靶点预后情况,并开发乳腺癌骨转移的风险预测模型。结果 西黄丸中的多种成分可作用于乳腺癌骨转移135个分子靶点,与196个乳腺癌骨转移差异miRNA构建出2964组miRNA-mRNA互作关系,锚定了10个Hub基因与95个miRNA,构建出175组miRNA-mRNA核心关系。Lasso回归聚焦出ADRB1是乳腺癌骨转移患者的独立预后因子,具有良好的诊断价值及生存预后价值,Cox回归分析发现乳腺癌的M分期、年龄是主要危险因素,而ADRB1高表达为保护因素,三者与患者总生存时间显著相关。基于8个miRNA(hsa-miR-500a-5p、hsa-miR-629-3p、hsa-miR-4665-5p、hsa-miR-3615、hsa-let-7d-5p、hsa-miR-93-3p、hsa-miR-141-3p、hsa-miR-183-3p)开发预后模型,以评估乳腺癌骨转移的预后。结论 本研究阐述了西黄丸干预乳腺癌骨转移的分子机制。其机制与其多组分调控ADRB1等多靶点,参与多生命进程有关,以mi RNA-mRNA互作模式共同调控乳腺癌骨转移不良预后。本研究还建立了乳腺癌骨转移预测模型,为开发治疗乳腺癌骨转移药物以及乳腺癌骨转移生物标志物的确定提供了潜在价值。 |
| 关键词: 乳腺癌 骨转移 西黄丸 生物信息学 网络药理学 列线图 |
| DOI：10.3969/j.issn.1674-070X.2022.12.014 |
| Received:May 07, 2022 |
| 基金项目:国家自然科学基金青年科学基金项目(82205128); 湖南省教育厅科学研究项目重点项目(19A383); 湖南省卫生健康委员会课题(20200754); 湖南省高等学校“双一流”学科建设项目(湘教通[2018]469号); 长沙市自然科学基金项目(kq202461) |
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| Molecular mechanism and prognosis of Xihuang Pill intervening breast cancer with bone metastasis based on miRNA-mRNA |
| DENG Xianguang,LIU Lifang,YUAN Bo |
| (Mammary Department, The First Hospital of Hunan University of Chinese Medicine, Changsha, Hunan 410007, China) |
| Abstract: |
| Objective Based on the miRNA-mRNA interaction model, this study clarified the molecular mechanism of Xihuang Pill intervening breast cancer with bone metastasis and analyzed the prognosis, so as to provide a theoretical basis for the determination of drug intervening targets and biomarkers of breast cancer with bone metastasis.Methods Synthesizing databases of GEO, TCGA, TargetScan, GeneCards, OMIM, TCMSP, STRING and HPA, protein-protein interaction(PPI) analysis, Hub gene topology analysis, gene ontology(GO) and Kyoto encyclopedia of genes and genomes(KEGG) enrichment analysis were carried by R language and Cytoscape software, through which the miRNA-mRNA interaction relationship for the molecular targets of Xihuang Pill intervening breast cancer with bone metastasis were constructed. Further, TCGA database was used to analyze the differential expression of molecular targets in tumor tissue and normal tissue, and HPA database was used to corroborate the immunohistochemical results. Finally, combined with patients' clinical information, the prognostic relevance of the molecular targets after Lasso regression was analyzed, and univariate Cox regression was used to analyze the clinical information and the prognosis of the molecular targets.Then a risk prediction model for breast cancer with bone metastasis was developed.Results Multiple components of Xihuang Pill acted on 135 molecular targets of breast cancer with bone metastasis, and these targets constructed 2964 groups of miRNA-mRNA interactions with 196 differential miRNAs. Moreover, 10 Hub genes and 95 miRNAs were anchored, which constructed 175 groups of miRNA-mRNA core relationships. Lasso regression focused on ADRB1 as an independent prognostic factor for breast cancer with bone metastasis, which had good diagnostic value and predictive value for survival prognosis. Cox regression found that the M stage of breast cancer and age were the main risk factors, while the high expression of ADRB1 was a protective factor. They were significantly related to the patient's overall survival. Finally, based on 8 miRNAs(hsa-miR-500a-5p, hsa-miR-629-3p, hsa-miR-4665-5p, hsa-miR-3615, hsa-let-7d-5p, hsa-miR-93-3p, hsa-miR-141-3p, hsa-miR-183-3p), a prognostic model was developed that can predict the poor prognosis of breast cancer with bone metastasis.Conclusion This study explained the molecular mechanism of Xihuang Pill intervening breast cancer with bone metastasis. The mechanism is related to multiple components of Xihuang Pill regulating various targets such as ADRB1, and participating in multi-life processes. Besides, the miRNA-mRNA interaction model regulates the prognosis of breast cancer with bone metastasis. More importantly, a predictive model has been developed in the study, which provides potential value for the exploration of medication and the determination of biomarkers for breast cancer with bone metastasis. |
| Key words: breast cancer bone metastasis Xihuang Pill bioinformatics network pharmacology nomogram |
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