膀胱癌ceRNA网络的构建和相关lncRNAs的筛选

Construction of ceRNA network and screening of lncRNAs in bladder cancer

目的:探讨膀胱癌差异表达的长链非编码RNA(long non-coding RNAs,lncRNAs)、微小RNA(microRNAs,miRNAs)和竞争性内源RNA(competing endogenous RNA,ceRNA)之间的相互作用机制,筛选潜在的lncRNA生物标志物。方法:使用生物信息学方法对多种数据库进行数据挖掘,得到膀胱癌差异表达的lncRNAs、miRNAs和mRNAs,并构建lncRNA-miRNA-mRNA的ceRNA调控网络。为了分析ceRNA网络行使的生物学功能,对ceRNA网络中的mRNAs进行基因本体(gene ontology,GO)和京都基因与基因组百科全书(Kyoto encyclopedia of genes and genomes,KEGG)分析并构建蛋白质相互作用(protein-protein interactions,PPI)网络。对ceRNA网络中的lncRNAs进行Kaplan-Meier生存曲线分析,筛选出与膀胱癌患者预后存在显著相关性的lncRNAs。结果:ceRNA网络中包括了17个lncRNAs、32个miRNAs和78个mRNAs。GO功能分析发现相关失调基因主要集中在蛋白丝氨酸/苏氨酸激酶途径、酪氨酸激酶途径等方面。KEGG通路富集分析结果显示这些基因集中在MAPK信号途径、脂质和动脉粥样硬化通路等方面。PPI网络中可以看出核心蛋白质主要围绕在MAPK1、HSPA8和HNRNPD等方面。通过Kaplan-Meier生存曲线分析发现共有6个lncRNAs与膀胱癌患者预后存在显著相关性,分别为C3orf35、ZBTB20-AS1、LINC00112、ARHGAP5-AS1、ARAP1-AS2和CYB561D2。结论:不同的lncRNAs参与了膀胱癌的发病机制;构建的ceRNA调控网络有助于增加对膀胱癌发病分子机制的认识;筛选的lncRNAs为后续的实验研究提供了基础。

Objective:The interaction mechanism between differentially expressed long non-coding RNAs(lncRNAs),microRNAs(miRNAs),and competing endogenous RNA(mRNAs)in bladder cancer was researched,potential lncRNA biomarkers were screened and their pathogenesis was explored.Methods:To obtain differentially expressed lncRNAs,miRNAs,and mRNAs in bladder cancer and construct a ceRNA regulatory network of lncRNA-miRNA-mRNA,bioinformatics methods were used to perform data mining on various databases.To analyze the biological functions of the ceRNA network,mRNAs in the ceRNA network were zanalyzed by gene ontology(GO)and Kyoto encyclopedia of genes and genomes(KEGG)and were constructed protein-protein interactions(PPI)network.lncRNAs in the ceRNA network were analyzed by the Kaplan-Meier survival curve and significantly correlated lncRNAs related to the prognosis of bladder cancer patients were screened from the ceRNA network.Results:The ceRNA network constructed in this study included 17 lncRNAs,32 miRNAs,and 78 mRNAs.GO function anotation showed that the related dysregulated genes were mainly concentrated in the protein serine/threonine kinase pathway,tyrosine kinase pathway,and so on.KEGG pathway enrichment analysis showed that these genes were concentrated in the MAPK signaling pathway,lipid,and atherosclerosis pathways.It can be seen from the PPI network that the core proteins mainly focus on MAPK1,HSPA8,and HNRNPD.Kaplan-Meier survival curve analysis showed that six lncRNAs were significantly correlated with the prognosis of bladder cancer patients,namely C3orf35,ZBTB20-AS1,LINC00112,ARHGAP5-AS1,ARAP1-AS2,and CYB561D2.Conclusions:Different lncRNAs are involved in the pathogenesis of bladder cancer.The construction of the ceRNA regulatory network helps to increase the understanding of the molecular mechanism of bladder cancer.The screened lncRNAs may become biomarkers for the diagnosis of bladder cancer and new targets for treatment.