miR-486-5p的靶基因预测及其在胰腺腺癌中作用的生物信息学分析

Prediction of target gene of miR-486-5p and bioinformatics analysis of their roles in pancreatic adenocarcinoma

背景与目的:胰腺癌是癌症相关性死亡的主要原因之一,是消化系统恶性程度最高的肿瘤,其主要的病理类型为胰腺腺癌(PAAD),预后较差。miR-486-5p在不同癌症中起重要的作用,但尚缺乏miR-486-5p在PAAD中的研究报告。本研究通过生物信息学方法探寻miR-486-5p的靶基因并分析靶基因在PAAD中的表达及意义。方法:使用PROGmiRV2数据库分析miR-486-5p与PAAD预后的相关性。综合运用多个数据平台来预测miR-486-5p的靶基因,并使用DAVID在线数据库对筛选出的靶基因进行基因本体论(GO)富集分析和京都基因与基因组百科(KEGG)信号通路分析,再以STRING数据库构建靶基因蛋白质-蛋白质相互作用(PPI)网络,并利用Cytoscape软件进行可视化编辑,筛选PPI网络中的核心基因,最后验证筛选出的核心基因,找出与PAAD预后相关的核心基因。结果:miR-486-5p低表达PAAD患者的总生存时间较miR-486-5p高表达患者明显缩短(P<0.05)。得到至少被3个数据库预测到的靶基因数目共187个。GO分析显示,靶基因主要参与蛋白质稳定、蛋白质磷酸化、RNA聚合酶II启动子的转录正调节及凋亡过程的负调节等生物学过程;KEGG分析显示靶基因主要参与FOXO信号通路、p53信号通路、Ras信号通路及PI3K-Akt信号通路等。miR-486-5p潜在靶基因的蛋白网络分析发现,SIRT1、PTEN、SMAD2、CSNK2A1、SE RPINE1是PPI网络中关键靶基因;进一步通过GEPIA验证发现CSNK2A1、SERPINE1在PAAD组织中均明显上调(均P<0.05),这些基因的高表达与PAAD患者的总体存活和无病生存相关(均P<0.05),CSNK2A1和SERPINE1的高表达的PAAD患者有更差的预后。结论:miR-486-5p通过对靶向基因的调控,作用于PAAD患者体内多种信号通路的网络,参与PAAD的发生和发展,影响PAAD患者的预后。

Background and Aims:Pancreatic cancer is one of the main causes of cancer-related death.It is the most malignant tumor of the digestive system.Its main pathological type is pancreatic adenocarcinoma(PAAD),which has a dismal prognosis.MiR-486-5p plays an important role in different cancers,but there is still no research report on miR-486-5p in PAAD so far.This study was conducted to explore the target genes of miR-486-5p and analyze the expression and significance of its target genes in PAAD by bioinformatics approaches.Methods:The correlation between miR-486-5p and the prognosis of PAAD was analyzed using the PROGmiRV2 database.The target genes of miR-486-5p were predicted by combined use of multiple data platforms,and then,the gene ontology(GO)enrichment analysis and Kyoto Gene and Genome Encyclopedia(KEGG)signal pathway analysis were performed for the selected target genes using the DAVID online database.After that,the protein-protein interaction(PPI)network of the target genes was constructed using the STRING database,and visualized using Cytoscape software for to screen the core genes in the PPI network.Finally,the candidate genes were verified and picked up to find the core genes related to the prognosis of PAAD.Results:The overall survival time of PAAD patients with low miR-486-5p expression was shorter than that of PAAD patients with high miR-486-5p expression(P<0.05).A total of 187 target genes were obtained,which were predicted by at least 3 different databases.Go analysis showed that the predicted target genes were mainly involved in the biological processes such as protein stability,protein phosphorylation,positive regulation of RNA polymerase II promoter transcription and negative regulation of apoptosis;KEGG analysis showed that the target genes were mainly involved in FOXO signaling pathway,p53 signal pathway,Ras signaling pathway,and PI3K-Akt signaling pathway.Protein network analysis of potential target genes of miR-486-5p showed that SIRT1,PTEN,SMAD2,CSNK2A1 and SERPINE1 were key target genes in PPI network.Further GEPIA verification revealed that CSNK2A1 and SERPINE1 were significantly up-regulated in PAAD tissues(all P<0.05).The high expressions of these genes were associated with the overall and disease-free survival in patients with PAAD(all P<0.05),and those with high expressions of CSNK2A1 and SERPINE1 had worse prognosis.Conclusion:MiR-486-5p acts on the network of multiple signaling pathways in PAAD patients through the regulation of targeted genes,participates in the occurrence and development of PAAD,and affects the prognosis of PAAD patients.