结直肠癌发病相关关键lncRNA的筛选和鉴定:基于肿瘤基因图谱数据库的生物信息学分析
|
摘要
目的探讨长链非编码RNA(lncRNA)在结直肠癌(CRC)中的表达特征及其对患者生存预后判断的潜在价值。方法下载肿瘤基因图谱(TCGA)中CRC相关的RNA序列(RNA-seq)数据,进行lncRNA表达差异、功能、通路富集、调控网络及lncRNA-mRNA共表达分析,同时分析lncRNA差异表达对CRC患者预后的影响。结果对TCGA 453个CRC临床样本数据进行分析,提示有119个lncRNA存在差异性表达,lncRNA和编码基因存在共表达关系,对基因富集性分析发现,lncRNA参与细胞的多个生物学行为;16个lncRNA对患者生存预后显著相关,其中3个lncRNA BVES-AS1、HAND2-AS1和MAMDC2-AS1为关键lncRNA,可作为预后判断的标志物,同时与mi RNA、coding gene存在紧密的调控网络。结论 lncRNA在CRC中存在差异性表达,起着重要的调控作用,在CRC患者诊断、靶向治疗及预后判断方面具有潜在的应用价值。
Objective To expore the lncRNA expression profiles and features in CRC tissues and their potential value associated with prognosis assessment. Methods The differential expression, functional and pathway enrichment, interaction network and lncRNA-mRNA co-expression of lncRNA wereanalyzed using RNA-seq data from TCGA. The prognosis changes of CRC patients induced by the differential expression level of lncRNA wereanalyzed. Results TCGA RNA-seq data from 453 specimens of CRC patients showed that there were 119 lncRNA which expressed differentially. lncRNA and coding gene had the relation of co-expression. lncRNA played various roles in biological features of cells. There existed lncRNA-miRNA-mRNA regulatory network. 16 of these lncRNA had potential value on the prognosis of CRC patients, 3 of them were key lncRNA,which were BVES-AS1, HAND2-AS1 and MAMDC2-AS1. They could be seemed as the biomarkers for prognosis of CRC patients. They also had close relations with the miRNA and coding gene. Conclusion lncRNA express differently in CRC tissues, and play an important role in biological feature of CRC cells, which have potential value in diagnosis, targeted therapy and prognosis of CRC patients.
Objective To expore the lncRNA expression profiles and features in CRC tissues and their potential value associated with prognosis assessment. Methods The differential expression, functional and pathway enrichment, interaction network and lncRNA-mRNA co-expression of lncRNA wereanalyzed using RNA-seq data from TCGA. The prognosis changes of CRC patients induced by the differential expression level of lncRNA wereanalyzed. Results TCGA RNA-seq data from 453 specimens of CRC patients showed that there were 119 lncRNA which expressed differentially. lncRNA and coding gene had the relation of co-expression. lncRNA played various roles in biological features of cells. There existed lncRNA-miRNA-mRNA regulatory network. 16 of these lncRNA had potential value on the prognosis of CRC patients, 3 of them were key lncRNA,which were BVES-AS1, HAND2-AS1 and MAMDC2-AS1. They could be seemed as the biomarkers for prognosis of CRC patients. They also had close relations with the miRNA and coding gene. Conclusion lncRNA express differently in CRC tissues, and play an important role in biological feature of CRC cells, which have potential value in diagnosis, targeted therapy and prognosis of CRC patients.
引文
[1]Tang RX,Chen WJ,He RQ,et al.Identification of a RNA-Seq based prognostic signature with five lncRNAs for lung squamous cell carcinoma[J].Oncotarget,2017,8(31):50761-73.
[2]Lun CY,Smyth GK.It's DE-licious:a recipe for dierential expression analyses of RNA-seq experiments using quasi-likelihood methods in edgeR[J].Methods Mol Biol,2016,1418(4):391-416.
[3]Pohar M,Stare J.Relative survival analysis in R[J].Comput Methods Programs Biomed,2006,81(3):272-8.
[4]Pearson K.Notes on regression and inheritance in the case of two parents[J].Proceed Royal Society London,1895,19(58):240-2.
[5]Shannon P,Markiel A,Ozier O,et al.Cytoscape:a software environment for integrated models of biomolecular interaction networks[J].Genome Res,2003,13(11):2498-504.
[6]Yu G,Wang LG,Han Y,et al.clusterProfiler:an R package for comparing biological themes among gene clusters[J].OMICS,2012,16(5):284-7.
[7]Chen EY,Tan CM,Kou Y,et al.Enrichr:interactive and collaborative HTML5 gene list enrichment analysis tool[J].BMCBioinformatics,2013,14(2):128-34.
[8]Enright AJ,John B,Gaul U,et al.MicroRNA targets in Drosophila[J].Genome Biol,2003,5(1):R1-8.
[9]Uziela K,Honkela A.Probe region expression estimation for RNA-Seq data for improved microarray comparability[J].PLoS One,2015,10(5):e0126545-9.
[10]Yang F,Lv SX,Lv L,et al.Identification of lncRNA FAM83H-AS1 as a novel prognostic marker in luminal subtype breast cancer[J].Onco Targets Ther,2016,9(11):7039-45.
[11]Kogo R,Shimamura T,Mimori K,et al.Long noncoding RNAHOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers[J].Cancer Res,2011,71(20):6320-6.
[12]Xi WD,Liu YJ,Sun XB,et al.Bioinformatics analysis of RNA-seq data revealed critical genes in colon adenocarcinoma[J].Eur Rev Med Pharmacol Sci,2017,21(13):3012-20.
[13]Lian Y,Yan C,Ding J,et al.A novel lncRNA,LL22NC03-N64E91,represses KLF2 transcription through binding with EZH2in colorectal cancer[J].Oncotarget,2017,8(35):59435-45.
[14]Lee S,Midas PY.Mining differentially activated subpaths of KEGG pathways from multi-class RNA-seq data[J].Methods,2017,124(1):13-24.
[15]Hong SJ,Chen XN,Jin L,et al.Canonical correlation analysis for RNA-seq co-expression networks[J].Nucleic Acids Res,2013,41(8):e95-103.
[16]Glover AR,Zhao JT,Ip JC,et al.Long noncoding RNA profiles of adrenocortical cancer can be used to predict recurrence[J].Endocr Relat Cancer,2015,22(1):99-109.
[17]Zhang W,Chang JW,Lin LL,et al.Network-Based isoform quantification with RNA-Seq data for cancer transcriptome analysis[J].PLoS Comput Biol,2015,11(12):e1004465-73.
[18]Lopes-Ramos C,Koyama FC,Habr-Gama AA,et al.Comprehensive evaluation of the effectiveness of gene expression signatures to predict complete response to neoadjuvant chemoradiotherapy and guide surgical intervention in rectal cancer[J].Cancer Genet,2015,208(6):319-26.
[19]Li JW,Xue W,Lv JL,et al.Identification of potential long noncoding RNA biomarkers associated with the progression of colon cancer[J].Oncotarget,2017,8(44):75834-43.
[20]Hosseini ES,Meryet-Figuiere M,Sabzalipoor H,et al.Dysregulated expression of long noncoding RNAs in gynecologic cancers[J].Mol Cancer,2017,16(1):107-12.
[21]Zhang M,Liu Y,Yu B,et al.Over-expression of long non-coding RNA GAPLINC promotes colorectal cancer cell metastasis and poor prognosis[J].Int J Clin Exp Med,2016,9(2):3203-8.
[22]Hao LY,Fu JY,Tian YW,et al.Systematic analysis of lncRNAs,miRNAs and mRNAs for the identification of biomarkers for osteoporosis in the mandible of ovariectomized mice[J].Int J Mol Med,2017,40(3):689-702.
[23]Guo QY,Cheng Y,Liang T,et al.Comprehensive analysis of lncRNA-mRNA co-expression patterns identifies immuneassociated lncRNA biomarkers in ovarian cancer malignant progression[J].Sci Rep,2015,5(20):17683-92.
[24]Zhu M,Chen Q,Liu X,et al.lncRNA H19/miR-675 axis represses prostate cancer metastasis by targeting TGFBI[J].FEBS J,2014,281(16):3766-75.
[25]Menges CW,Kadariya Y,Altomare DA,et al.Tumor suppressor alterations cooperate to drive aggressive mesotheliomas with enriched cancer stem cells via a p53-miR-34a-c-Met axis[J].Cancer Res,2014,74(4):1261-71.
[2]Lun CY,Smyth GK.It's DE-licious:a recipe for dierential expression analyses of RNA-seq experiments using quasi-likelihood methods in edgeR[J].Methods Mol Biol,2016,1418(4):391-416.
[3]Pohar M,Stare J.Relative survival analysis in R[J].Comput Methods Programs Biomed,2006,81(3):272-8.
[4]Pearson K.Notes on regression and inheritance in the case of two parents[J].Proceed Royal Society London,1895,19(58):240-2.
[5]Shannon P,Markiel A,Ozier O,et al.Cytoscape:a software environment for integrated models of biomolecular interaction networks[J].Genome Res,2003,13(11):2498-504.
[6]Yu G,Wang LG,Han Y,et al.clusterProfiler:an R package for comparing biological themes among gene clusters[J].OMICS,2012,16(5):284-7.
[7]Chen EY,Tan CM,Kou Y,et al.Enrichr:interactive and collaborative HTML5 gene list enrichment analysis tool[J].BMCBioinformatics,2013,14(2):128-34.
[8]Enright AJ,John B,Gaul U,et al.MicroRNA targets in Drosophila[J].Genome Biol,2003,5(1):R1-8.
[9]Uziela K,Honkela A.Probe region expression estimation for RNA-Seq data for improved microarray comparability[J].PLoS One,2015,10(5):e0126545-9.
[10]Yang F,Lv SX,Lv L,et al.Identification of lncRNA FAM83H-AS1 as a novel prognostic marker in luminal subtype breast cancer[J].Onco Targets Ther,2016,9(11):7039-45.
[11]Kogo R,Shimamura T,Mimori K,et al.Long noncoding RNAHOTAIR regulates polycomb-dependent chromatin modification and is associated with poor prognosis in colorectal cancers[J].Cancer Res,2011,71(20):6320-6.
[12]Xi WD,Liu YJ,Sun XB,et al.Bioinformatics analysis of RNA-seq data revealed critical genes in colon adenocarcinoma[J].Eur Rev Med Pharmacol Sci,2017,21(13):3012-20.
[13]Lian Y,Yan C,Ding J,et al.A novel lncRNA,LL22NC03-N64E91,represses KLF2 transcription through binding with EZH2in colorectal cancer[J].Oncotarget,2017,8(35):59435-45.
[14]Lee S,Midas PY.Mining differentially activated subpaths of KEGG pathways from multi-class RNA-seq data[J].Methods,2017,124(1):13-24.
[15]Hong SJ,Chen XN,Jin L,et al.Canonical correlation analysis for RNA-seq co-expression networks[J].Nucleic Acids Res,2013,41(8):e95-103.
[16]Glover AR,Zhao JT,Ip JC,et al.Long noncoding RNA profiles of adrenocortical cancer can be used to predict recurrence[J].Endocr Relat Cancer,2015,22(1):99-109.
[17]Zhang W,Chang JW,Lin LL,et al.Network-Based isoform quantification with RNA-Seq data for cancer transcriptome analysis[J].PLoS Comput Biol,2015,11(12):e1004465-73.
[18]Lopes-Ramos C,Koyama FC,Habr-Gama AA,et al.Comprehensive evaluation of the effectiveness of gene expression signatures to predict complete response to neoadjuvant chemoradiotherapy and guide surgical intervention in rectal cancer[J].Cancer Genet,2015,208(6):319-26.
[19]Li JW,Xue W,Lv JL,et al.Identification of potential long noncoding RNA biomarkers associated with the progression of colon cancer[J].Oncotarget,2017,8(44):75834-43.
[20]Hosseini ES,Meryet-Figuiere M,Sabzalipoor H,et al.Dysregulated expression of long noncoding RNAs in gynecologic cancers[J].Mol Cancer,2017,16(1):107-12.
[21]Zhang M,Liu Y,Yu B,et al.Over-expression of long non-coding RNA GAPLINC promotes colorectal cancer cell metastasis and poor prognosis[J].Int J Clin Exp Med,2016,9(2):3203-8.
[22]Hao LY,Fu JY,Tian YW,et al.Systematic analysis of lncRNAs,miRNAs and mRNAs for the identification of biomarkers for osteoporosis in the mandible of ovariectomized mice[J].Int J Mol Med,2017,40(3):689-702.
[23]Guo QY,Cheng Y,Liang T,et al.Comprehensive analysis of lncRNA-mRNA co-expression patterns identifies immuneassociated lncRNA biomarkers in ovarian cancer malignant progression[J].Sci Rep,2015,5(20):17683-92.
[24]Zhu M,Chen Q,Liu X,et al.lncRNA H19/miR-675 axis represses prostate cancer metastasis by targeting TGFBI[J].FEBS J,2014,281(16):3766-75.
[25]Menges CW,Kadariya Y,Altomare DA,et al.Tumor suppressor alterations cooperate to drive aggressive mesotheliomas with enriched cancer stem cells via a p53-miR-34a-c-Met axis[J].Cancer Res,2014,74(4):1261-71.