膀胱癌circRNAs介导的ceRNA网络及预后评估模型的构建

doi:10.6040/j.issn.1671-7554.0.2021.0231

摘要/Abstract

摘要： 目的探究膀胱癌中差异性表达的环状RNAs(circRNAs),并构建circRNAs介导的ceRNA网络及预后评估模型。方法下载并分析基因表达数据库(GEO)和癌症基因组图谱(TCGA)中膀胱癌RNA测序数据,以|log2 fold change(log2FC)|>1、P-value<0.05为纳入标准,筛选RNA差异表达谱。整合TCGA膀胱癌RNA差异分析数据及CircInteractome等公共数据库数据,构建circRNA-miRNA-mRNA ceRNA网络,通过GEO与TCGA对网络中mRNAs进行功能富集分析。利用String数据库挖掘ceRNA网络分子的相互作用关系。采用Cox回归分析筛选预后相关mRNAs,并构建膀胱癌预后风险评估模型;利用“time ROC”软件包绘制ROC曲线,对模型效能进行评估。结果通过2个GEO数据集的差异分析,共筛选到4个circRNAs,分别是hsa_circ_0102787、hsa_circ_0103114、hsa_circ_0102402与hsa_circ_0104387。通过公共数据库及TCGA差异分析,构建了由circRNAs介导的ceRNA网络,包含4个circRNAs、23个miRNAs和86个mRNAs;功能富集分析显示该网络mRNAs涉及多个与肿瘤调控相关的生物学过程;网络中mRNAs存在相互作用关系,生存分析显示6个mRNAs与膀胱癌预后相关。以“风险评分=(-0.356 9)×ABRACL+(-0.264 4)×MAP3K8”构建膀胱癌预后风险评估模型,Kaplan-Meier曲线提示高评分组预后差(P<0.001),模型5年总体生存率的AUC=0.744。结论发掘4个膀胱癌中表达失调的circRNAs,构建了膀胱癌相关circRNA-miRNA-mRNA网络及预后评估模型,为揭示膀胱癌发生发展的分子机制及寻找新的诊断、预后标志物奠定了理论基础。

关键词: 膀胱癌, circRNAs, ceRNA, 预后, Cox风险评估模型

Abstract: Objective To identify the differentially expressed circular RNAs(circRNAs)and construct a circRNAs-mediated ceRNA network and a prognostic assessment model. Methods Data were downloaded from Gene Expression Omnibus(GEO)and The Cancer Genome Atlas(TCGA)database. Differential expressed analysis was performed to explore the differentially expressed RNAs in bladder cancer tissues with the standard of |log2 fold change(log2FC)|>1, P<0.05. Based on multiple detabases, such as TCGA and CircInteractome, the circRNA-miRNA-mRNA ceRNA network was constructed, and functional enrichment analysis of mRNAs was conducted. Subsequently, the relationship of mRNAs in ceRNA network was analyzed through the String database. The mRNAs related to prognosis were screened with univariate Cox regression model, and a prognostic assessment model was constructed. A ROC curve was drawn with “time ROC” package to evaluate the effectiveness of the model. Results Differential expressed analysis screened out 4 circRNAs, including hsa_circ_0102787, hsa_circ_0103114, hsa_circ_0102402 and hsa_circ_0104387. A ceRNA network was constructed, which contained 4 circRNAs, 23 miRNAs and 86 mRNAs. Functional enrichment analysis showed those mRNAs participated in several cancer-related pathways. The interaction between mRNAs in the ceRNA network was visualized by PPI network. Survival analysis revealed that 6 mRNAs were related to the prognosis of bladder cancer. Then, a prognostic assessment model was constructed based on “the risk score=(-0.356 9)×ABRACL+(-0.264 4)×MAP3K8.” Kaplan Meier analysis showed patients with high risks had a poor prognosis(P<0.001), and the AUC of the five-year overall survival rate was 0.744. Conclusion This study identififed 4 differentially expressed circRNAs, and constructed a circRNA-miRNA-mRNA network and a prognostic assessment model, which provides a new insight for the exploration of the occurrence and development of bladder cancer.

Key words: Bladder cancer, circRNAs, ceRNA, Prognosis, Cox regression model

中图分类号:

R737.14

米琦,史爽,李娟,李培龙,杜鲁涛,王传新. 膀胱癌circRNAs介导的ceRNA网络及预后评估模型的构建[J]. 山东大学学报 (医学版), 2021, 59(6): 94-102.

MI Qi, SHI Shuang, LI Juan, LI Peilong, DU Lutao, WANG Chuanxin. Construction of circRNA-mediated ceRNA network and prognostic assessment model for bladder cancer[J]. Journal of Shandong University (Health Sciences), 2021, 59(6): 94-102.

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