基于miRNA-mRNA调控关系对与Cox回归模型的宫颈鳞状细胞癌预后生物标志物综合分析

doi:10.12280/gjfckx.20201204

摘要/Abstract

摘要：

目的：探究微小RNA（miRNA）-信使RNA（mRNA）关系对在宫颈鳞状细胞癌（CESC）中的表达,分析其预测CESC预后的意义。方法：利用癌症和肿瘤基因图谱（TCGA）数据库筛选CESC和正常宫颈组织中miRNA和mRNA的差异表达谱,利用miRTarBase、TargetScan和miRDB数据库验证miRNA与靶向mRNA的相互作用关系,并通过Cytoscape软件可视化,采用Kaplan-Meier生存分析确定CESC的预后标志物,构建与CESC预后相关的miRNA-mRNA调控网络,并对筛选出的mRNA进行基因本体功能（GO）富集分析和京都基因与基因组百科全书（KEGG）通路富集分析。结果：通过比较CESC组织与正常宫颈组织,共检测到4个miRNA可纳入预后风险评分模型,生存分析筛选出9个与CESC预后相关的差异表达mRNA,最终得到与CESC预后紧密相关的4个miRNA-mRNA调控关系对,hsa-miR-505-5p的靶向mRNA为染色质结构域蛋白8（CBX8）,hsa-miR-142-3p分别靶向Ⅰ型血小板结合蛋白基序的解聚蛋白样金属蛋白酶3（ADAMTS3）、蛋白酪氨酸磷酸酶受体B（PTPRB）和SEC23同源物A（SEC23A）。生物学功能和通路分析显示,差异表达的mRNA主要在生物学过程和磷脂酰肌醇3激酶-蛋白激酶B（PI3K-Akt）、人乳头瘤病毒（HPV）感染的通路中显著富集。结论：miRNA-mRNA关系对与CESC预后相关,可作为今后CESC发病机制研究的新角度以及监测预后的有效指标。

关键词: 宫颈肿瘤, 癌症和肿瘤基因图谱数据库, Kaplan-Meiers评估, 预后, 微RNAs, RNA,信使

Abstract:

Objective: To explore the expression of microRNA(miRNA)-messenger RNA(mRNA) and predict its prognostic significance in cervical squamous carcinoma (CESC), analyze its significance in predicting the prognosis of CESC. Methods: TCGA database was used to screen the differential expression profiles of miRNA and mRNA in CESC and normal cervical tissue. The interaction between miRNA and targeted mRNA was verified by miRTarBase, TargetScan and miRDB databases. The prognostic markers of CESC were determined by Kaplan-Meier survival analysis and visualized by Cytoscape software. Construction the miRNA-mRNA regulatory network related to the prognosis of CESC, the selected mRNAs were analyzed by gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment. Results: Four miRNAs and nine mRNAs differentially expressed in CESC and normal tissues were detected. Four miRNA-mRNA axes closely related to the prognosis of CESC were obtained. The target mRNA of hsa-miR-505-5p was CBX8, and hsa-miR-142-3p targeted ADAMTS3, PTPRB and SEC23A respectively. Biological function and pathway analysis showed that the differentially expressed mRNAs were mainly enriched in biological process and PI3K-Akt pathway, HPV infection pathway. Conclusions: Above miRNA-mRNA axes obtained in this study are related to the prognosis of CESC, which can be used as a new perspective for the study of the pathogenesis and an effective indicator for monitoring the prognosis of CESC.

Key words: Uterine cervical neoplasms, The cancer genome atlas databases, Kaplan-Meier estimate, Prognosis, MicroRNAs, RNA,messenger

李元幸, 牛晓辰, 常晶晶, 雒海瑕, 王伟. 基于miRNA-mRNA调控关系对与Cox回归模型的宫颈鳞状细胞癌预后生物标志物综合分析[J]. 国际妇产科学杂志, 2021, 48(5): 553-559.

LI Yuan-xing, NIU Xiao-chen, CHANG Jing-jing, LUO Hai-xia, WANG Wei. Comprehensive Analysis of Prognostic Biomarkers in Cervical Squamous Carcinoma Based on Aberrant MiRNA-mRNA Axes and Cox Regression Models[J]. Journal of International Obstetrics and Gynecology, 2021, 48(5): 553-559.

图/表 6

图1 CESC中差异表达的RNA聚类热图注：Type C 正常对照组,Type T CESC组。上图为miRNA,下图为mRNA。

图2 纳入预后模型的miRNA不同表达者的生存曲线及预后模型评价注：A~D分别为hsa-miR-505-5p、hsa-miR-142-3p、hsa-miR-532-5p和hsa-miR-3613-5p生存曲线,E为风险值生存曲线,F为CESC样本预后分析的ROC曲线,风险值AUC为0.872。

图3 CESC的miRNA-mRNA调控网络注：红色代表表达上调,绿色代表表达下调。

图4 与CESC预后相关的9个mRNA不同表达者的生存曲线

表1 miRNA-mRNA调控关系对

miRNA	mRNA	miRNA Logfc	mRNA Logfc
hsa-miR-505-5p	CBX8	-1.529 199 462	-2.705 845 009
hsa-miR-142-3p	ADAMTS3	3.301 570 739	-2.854 301 105
hsa-miR-142-3p	PTPRB	3.301 570 739	-2.705 845 009
hsa-miR-142-3p	SEC23A	3.301 570 739	-1.157 470 699

图5 mRNA功能富集气泡图

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