生物信息学在三阴性乳腺癌miRNA生物标志物筛选中的应用

Application of bioinformatics in screening of miRNA biomarkers in triple-negative breast cancer

目的:通过医学癌症数据库(TCGA)和基因表达数据库(GEO)分析三阴性乳腺癌(TNBC)中差异表达微小RNA(miRNAs)并预测其靶基因,探讨其生物学功能和分子机制,寻找TNBC预后相关靶点。方法:下载TCGA数据库中343项关于乳腺癌组织与癌旁组织相关的miRNAs表达数据,筛选乳腺癌与癌旁组织中差异表达的miRNAs;GEO数据库验证miRNAs在TNBC细胞 系的26种细胞株中的表达以及TNBC患者经过化疗前后血清中miRNAs的变化;通过基因本体(GO)功能注释及京都基因和基因组百科全书(KEGG)信号通路富集、蛋白质互作网络分析候选miRNAs的靶基因功能。结果:TCGA数据库,在乳腺癌组织中的miR-21-5p表达水平明显高于相邻癌旁组织(logFC=5.557,P<0.01);GEO数据库筛选,miR-21-5p在TNBC细胞 系中表达水平明显升高,在26种TNBC细胞株中超过20种细胞株相对表达水平>70000,TNBC患者 经联合化疗后miR-21-5p的表达水平明显降低(logFC=-5.07,P<0.01);GO分析,miR-21-5p主要在DNA复制、转录以及血管重构等方面发挥调控作用;KEGG富集分析,miR-21-5p主要通过促分裂原活化蛋白激酶(MAPK)和转化生长因子β(TGF-β)等通路影响TNBC的发生发展。结论:miR-21-5p在TNBC组织 中表达上调,在TNBC进展中发挥正调控作用,可能成为鉴定TNBC相关预后程度的关键生物学标志物。DUSP8等可能作为miR-21-5p的靶基因参与调控TNBC的发生发展。

Objective : To analyze the differentially expressed miRNAs in triple negative breast cancer (TNBC) and predict their target genes through The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, to explore their biological functions and molecular mechanisms, and to find the prognosis-related targets of TNBC. Methods : A total of 343 miRNAs expression data related to breast cancer tissue and adjacent tissue were downloaded from the TCGA database to screen the differentially expressed miRNAs in breast cancer and adjacent tissue. The GEO database was used to validate the expressions of miRNAs in 26 kinds of cell lines of TNBC and the changes in serum miRNAs in the TNBC patients before and after chemotherapy. The target gene function of candidate miRNAs was analyzed by Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) signal pathway enrichment and protein interaction network. Results : The TCGA database showed that the expression level of miR-21-5p in breast cancer tissue was significantly higher than that in adjacent tissue (logFC=5.557, P <0.01). The results of GEO database showed that the expression level of miR-21-5p increased in TNBC cell line was significantly higher;the relative expression levels in more than 20 kinds of cell lines from 26 TNBC cell lines were over 70 000, and the expression level of miR-21-5p in the TNBC patients after combined chemotherapy was significantly decreased(logFC=-5.07, P <0.01).The GO analysis showed that miR-21-5p played a regulatory role in DNA replication, transcription and vascular remodeling. The KEGG enrichment analysis showed that miR-21-5p mainly affected the occurrence and development of TNBC through mitogen activated protein kinase(MAPK) and transforming growth factor-β(TGF-β) pathw ays. Conclusion : miR-21-5p is up-regulated in TNBC tissue and plays a positive regulatory role in the progression of TNBC, which may be a key biomarker for identifying the prognostic extent of TNBC. DUSP8 may be involved in the regulation of the occurrence and development of TNBC as a target gene of miR-21-5p.