基于公共数据库的甲状腺癌预后风险基因筛选

Identification of prognostic risk genes for thyroid cancer based on public databases

背景与目的甲状腺癌的发病率呈逐年增长趋势,尽管其总体预后较好,但仍有部分患者因复发或转移而死亡。本研究旨在基于公共数据库应用生物信息学方法筛选甲状腺癌的预后风险基因。方法从癌症RNA测序关系(CRN)数据库下载甲状腺癌的蛋白编码基因RNA-seq数据,筛选甲状腺癌中差异表达的蛋白编码基因。通过DAVID数据库对差异表达的蛋白编码基因进行功能富集分析。用STRING数据库和Cytoscape软件构建差异表达蛋白编码基因之间的相互作用网络,分别用Cytoscape软件中的cytoHubba插件与ClueGO插件筛选核心基因,并对核心基因进行功能预测。用UALCAN数据库验证核心基因在甲状腺癌中的表达水平,通过GEPIA数据库对核心基因进行生存分析,分析核心基因的表达水平对甲状腺癌的生存时间有无影响。结果筛选共得到913个差异表达的蛋白编码基因。这些基因主要富集于调控小分子GTP酶介导的信号转导、Z膜、结合肌动蛋白和细胞色素P450介导的药物代谢。构建互作网络后,筛选出10个核心基因,分别为TP53、ESR1、FOS、SYP、PPARG、ACTB、GRIA1、NRXN1、HDAC3和KIT,其中TP53得分最高,为62,它们均在甲状腺癌组织中表达下调;预测显示核心基因TP53、ESR1、PPARG可能参与了基因沉默的负性调控,TP53、FOS可能参与了RNA聚合酶II对pri-miRNA的转录调控过程。UALCAN数据库验证结果显示,除TP53外,其余核心基因均在甲状腺癌组织中表达下调(均P<0.05),与CRN数据库中的表达结果一致。生存分析结果显示,KIT的高表达与甲状腺癌患者的无病生存期明显相关(P=0.012),而对其总体生存期无明显影响(P=0.85)。结论本研究筛选的蛋白编码基因KIT在甲状腺癌组织中呈低表达,其高表达与甲状腺癌的无病生存期密切相关,推测其可能成为甲状腺癌的预后风险标志物或治疗靶点。

Background and Aims The incidence of thyroid cancer is increasing over years.Although its overall prognosis is favorable,some patients still die due to recurrence or metastasis.The purpose of this study was to screen the prognostic risk genes for thyroid carcinoma using bioinformatics approaches based on public databases.Methods The protein-coding gene RNA-seq data of thyroid cancer were downloaded from Cancer RNA-Seq Nexus(CRN)database and the differentially expressed protein-coding genes were screened.Then,enrichment analysis of the differentially expressed protein-coding genes was performed using the DAVID database.Protein-protein interaction networks among the differentially expressed protein-coding genes were constructed and analyzed using STRING and Cytoscape.The hub genes and their functional prediction were screened by the Cytohubba and ClueGO plugins,respectively.The expression level of hub genes was verified in thyroid cancer based on the UALCAN database,and survival analysis of hub genes was conducted in the GEPIA database to analyze whether their expression had an impact on the survival time of thyroid cancer.Results A total of 913 differentially expressed protein-coding genes were obtained after screening.These genes were mainly involved in regulation of small GTPase mediated signal transduction,Z disc,actin binding and drug metabolism-cytochrome P450.After construction of interaction networks,10 hub genes were screened and they were TP53,ESR1,FOS,SYP,PPARG,ACTB,GRIA1,NRXN1,HDAC3 and KIT,of which TP53 had the highest score of 62.All of them were down-regulated in thyroid cancer tissue.Prediction results revealed that TP53,ESR1 and PPARG were probably involved in negative regulation of gene silencing,and TP53 and FOS were probably involved in the process of pri-miRNA transcription by RNA polymerase II.Results of verification in the UALCAN database showed that all except TP53,all other hub genes were down-regulated in thyroid cancer tissues(all P<0.05),which was consistent with the expression results in the CRN database.Results of survival analysis showed that high expression of KIT was significantly associated with disease-free survival of thyroid cancer patients(P=0.012),but had no significant effect on their overall survival(P=0.85).Conclusion The identified protein-coding gene KIT has a low expression in thyroid cancer tissue,and its high expression is closely associated with the disease-free survival of thyroid cancer,which is speculated to be a prognostic risk marker or therapeutic target for thyroid cancer.