基于TCGA数据库构建和分析胃癌相关ceRNAs网络
|
摘要
目的整合TCGA数据库中转录谱表达数据,建立lncRNA-miRNA-mRNA竞争性内源性RNA(ceRNA)网络,探讨lncRNA介导的ceRNA在胃癌中的功能作用和调控机制以及它们在预测胃癌预后方面的潜在应用。方法从TCGA数据库中获得375个胃癌组织及32个相邻胃组织的mRNA、lncRNA、miRNA的异常表达谱。构建胃癌中的lncRNA-mRNA-miRNA ceRNA网络。同时,利用DAVID数据库进行基因本体论(GO)和KEGG通路分析。结果本研究总共获得差异表达mRNA 2669条,lncRNA616条,miRNA 148条,并在胃癌中构建了差异表达的lncRNA-miRNA-mRNA ceRNA网络,该ceRNA网络共包含49个DElncRAN,21个DEmiRNA,61个DEmRNA。根据整体生存分析,49个DElncRNA中有6个,61个DEmRNA中有20个,21个DEmiRNA中有7个作为胃癌患者预后生物标志物(P<0.05)。进一步提取了ceRNA网络中的子网络,发现两个新的lncRNA被识别为关键基因,分别为lncRNA LINC00330和lncRNA MIR205HG。结论新识别的ceRNA网络将有助于更好地理解lncRNA介导的ceRNA调控机制在胃癌发病机制中的作用,lncRNA LINC00330,MIR205HG可能为胃癌发生发展中的关键分子。
Objective Through integrated the transcriptional expression data in the TCGA database,constructing lncRNA-mRNA-miRNA competitive endogenous RNA( ceRNA) network,to explore functional roles and regulatory mechanisms of lncRNA-mediated ceRNA in gastric cancer,as well as their potential application in predicting prognosis of gastric cancer.Methods The aberrant expression profiles of mRNA,lncRNA,and miRNA of 375 gastric cancer tissues and 32 adjacent stomach tissues were obtained from the TCGA database.Construct an lncRNA-mRNA-miRNA ceRNA network in gastric cancer was constructed. Meanwhile,Gene Ontology( GO) and KEGG pathway analysis were performed by using DAVID database.Results We identified a total of 2669 items of mRNA,616 items of lncRNA and 18 items of miRNA as differentially expressed profiles. An aberrant lncRNA-mRNA-miRNA ceRNA network was constructed in GC,and it was composed of 49 items of DElncRNA,21 items of DEmiRNA,and 61 items of DEmRNA.According to the overall survival analysis,6 items of DElncRNA,20 items of DEmRNA,and 7 items of DEmiRNA functioned as prognostic biomarkers for patients with GC( P< 0.05). We extracted the sub-network in the ceRNA network and found that two novel lncRNA were recognized as key genes.These were lncRNA LINC00330 and lncRNA MIR205 HG. Conclusions The novel recognized ceRNA network will help us to improve our understanding of lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of GC.LncRNA LINC00330 and MIR205 HG may be key molecules in the development of gastric cancer.
Objective Through integrated the transcriptional expression data in the TCGA database,constructing lncRNA-mRNA-miRNA competitive endogenous RNA( ceRNA) network,to explore functional roles and regulatory mechanisms of lncRNA-mediated ceRNA in gastric cancer,as well as their potential application in predicting prognosis of gastric cancer.Methods The aberrant expression profiles of mRNA,lncRNA,and miRNA of 375 gastric cancer tissues and 32 adjacent stomach tissues were obtained from the TCGA database.Construct an lncRNA-mRNA-miRNA ceRNA network in gastric cancer was constructed. Meanwhile,Gene Ontology( GO) and KEGG pathway analysis were performed by using DAVID database.Results We identified a total of 2669 items of mRNA,616 items of lncRNA and 18 items of miRNA as differentially expressed profiles. An aberrant lncRNA-mRNA-miRNA ceRNA network was constructed in GC,and it was composed of 49 items of DElncRNA,21 items of DEmiRNA,and 61 items of DEmRNA.According to the overall survival analysis,6 items of DElncRNA,20 items of DEmRNA,and 7 items of DEmiRNA functioned as prognostic biomarkers for patients with GC( P< 0.05). We extracted the sub-network in the ceRNA network and found that two novel lncRNA were recognized as key genes.These were lncRNA LINC00330 and lncRNA MIR205 HG. Conclusions The novel recognized ceRNA network will help us to improve our understanding of lncRNA-mediated ceRNA regulatory mechanisms in the pathogenesis of GC.LncRNA LINC00330 and MIR205 HG may be key molecules in the development of gastric cancer.
引文
[1]Torre LA,Bray F,Siegel RL,et al.Global cancer statistics,2012[J].CA:Cancer J Clin,2015,65(2):87-108.
[2]Chen W,Zheng R,Baade PD,et al.Cancer statistics in China,2015[J].CA:A Cancer J Clin,2016,66(2):115-132.
[3]Siegel RL,Miller KD,Jemal A.Cancer statistics,2016[J].CA:ACancer J Clin,2015,60(5):277-300.
[4]Caley DP,Pink RC,Trujillano D,et al.Long noncoding RNAs,chromatin,and development[J].The Scientific World J,2014,10(1):90.
[5]Yang L,Duff MO,Graveley BR,et al.Genomewide characterization of non-polyadenylated RNAs[J].Genome Biology,2011,12(2):R16.
[6]Salmena L,Poliseno L,Tay Y,et al.A ceRNA Hypothesis:The Rosetta Stone of a Hidden RNA Language?[J].Cell,2011,146(3):353-358.
[7]Ergun S,Oztuzcu S.Oncocers:ceRNA-mediated cross-talk by sponging miRNAs in oncogenic pathways[J].Tumor Biology,2015,36(5):3129-3136.
[8]Qi X,Zhang DH,Wu N,et al.ceRNA in cancer:possible functions and clinical implications[J].J Med Genet,2015,52(10):710-718.
[9]Zhang G,Li S,Lu J,et al.LncRNA MT1JP functions as a ceRNA in regulating FBXW7 through competitively binding to miR-92a-3p in gastric cancer[J].Mol Cancer,2018,17(1):87.
[10]Yang XZ,Cheng TT,He QJ,et al.LINC01133 as ceRNA inhibits gastric cancer progression by sponging miR-106a-3p to regulate APC expression and the Wnt/β-catenin pathway[J].Mol Cancer,2018,17(1):126.
[11]Li D,Yang M,Liao A,et al.Linc00483 as ceRNA regulates proliferation and apoptosis through activating MAPKs in gastric cancer[J].J Cell Mol Med,2018,22(8):3875-3886.
[12]Robinson MD,Mc Carthy DJ,Smyth GK.edgeR:a Bioconductor package for differential expression analysis of digital gene expression data[J].Bioinformatics,2010,26(1):139.
[13]Jeg gari A,Marks DS,Larsson E.miRcode:a map of putative microRNA target sites in the long non-coding transcriptome[J].Bioinformatics,2012,28(15):2062-2063.
[14]Hsu SD,Tseng YT,Shrestha S,et al.miRTar Base update 2014:an information resource for experimentally validated miRNA-target interactions[J].Nucleic Acids Res,2014,42:78-85.
[15]John B,Enright AJ,Aravin A,et al.Human MicroRNA targets[J].PLoS Biol,2004,2(11):e363.
[16]Park K,Kim KB.miRTar Hunter:a prediction system for identifying human microRNA target sites[J].Mol Cells,2013,35(3):195-201.
[17]Sh annon 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.
[18]Zhao Y,Liu Y,Lin L,et al.The lncRNA MACC1-AS1 promotes gastric cancer cell metabolic plasticity via AMPK/Lin28 mediated mRNA stability of MACC1[J].Mol Cancer,2018,17(1):69.
[19]Cao X,Xu J,Yue D.LncRNA-SNHG16 predicts poor prognosis and promotes tumor proliferation through epigenetically silencing p21 in bladder cancer[J].Cancer Gene Therapy,2017,25(1-2):1.
[20]Zhao Y,Wang H,Wu C,et al.Construction and investigation of lncRNA-associated ceRNA regulatory network in papillary thyroid cancer[J].Onco Rep,2018,39(3):1197-1206.
[21]Ghorbanmehr N,Gharbi S,AUID-Oho,et al.miR-21-5p,miR-141-3p,and miR-205-5p levels in urine-promising biomarkers for the identification of prostate and bladder cancer[J].Prostate,2018.
[22]Li L,Li S.miR-205-5p inhibits cell migration and invasion in prostatic carcinoma by targeting ZEB1[J].Oncol Lett,2018,16(2):1715-1721.
[23]Chu P,Liang A,Jiang A,et al.miR-205 regulates the proliferation and invasion of ovarian cancer cells via suppressing PTEN/SMAD4expression[J].Oncol Lett,2018,15(5):7571-7578.
[24]Su N,Qiu H,Chen Y,et al.miR-205 promotes tumor proliferation and invasion through targeting ESRRG in endometrial carcinoma[J].Oncol Rep,2013,29(6):2297-2302.
[25]Wu Z,Huang W,Wang X,et al.Circular RNA CEP128 acts as a sponge of miR-145-5p in promoting the bladder cancer progression via regulating SOX11[J].Mol Med,2018,24(1):40.
[26]Lu R,Ji Z,Li X,et al.miR-145 functions as tumor suppressor and targets two oncogenes,ANGPT2 and NEDD9,in renal cell carcinoma[J].J Cancer Res Clin Oncol,2014,140(3):387-397.
[27]Zhu N,Hou J,Wu Y,et al.Integrated analysis of a competing endogenous RNA network reveals key lncRNAs aspotential prognostic biomarkers for human bladder cancer[J].Medicine(Baltimore),2018,97(35):e11887.
[28]Di AS,Valenti F,Sacconi A,et al.Long Non-coding MIR205HGDepletes Hsa-miR-590-3p Leading to Unrestrained Proliferation in Head and Neck Squamous Cell Carcinoma[J].Theranostics,2018,8(7):1850-1868.
[29]贾业贵,许浪.YAP蛋白在不同恶性程度的胃癌组织中的表达及其死亡率的影响[J].热带医学杂志,2016,16(9):1174-1176.
[2]Chen W,Zheng R,Baade PD,et al.Cancer statistics in China,2015[J].CA:A Cancer J Clin,2016,66(2):115-132.
[3]Siegel RL,Miller KD,Jemal A.Cancer statistics,2016[J].CA:ACancer J Clin,2015,60(5):277-300.
[4]Caley DP,Pink RC,Trujillano D,et al.Long noncoding RNAs,chromatin,and development[J].The Scientific World J,2014,10(1):90.
[5]Yang L,Duff MO,Graveley BR,et al.Genomewide characterization of non-polyadenylated RNAs[J].Genome Biology,2011,12(2):R16.
[6]Salmena L,Poliseno L,Tay Y,et al.A ceRNA Hypothesis:The Rosetta Stone of a Hidden RNA Language?[J].Cell,2011,146(3):353-358.
[7]Ergun S,Oztuzcu S.Oncocers:ceRNA-mediated cross-talk by sponging miRNAs in oncogenic pathways[J].Tumor Biology,2015,36(5):3129-3136.
[8]Qi X,Zhang DH,Wu N,et al.ceRNA in cancer:possible functions and clinical implications[J].J Med Genet,2015,52(10):710-718.
[9]Zhang G,Li S,Lu J,et al.LncRNA MT1JP functions as a ceRNA in regulating FBXW7 through competitively binding to miR-92a-3p in gastric cancer[J].Mol Cancer,2018,17(1):87.
[10]Yang XZ,Cheng TT,He QJ,et al.LINC01133 as ceRNA inhibits gastric cancer progression by sponging miR-106a-3p to regulate APC expression and the Wnt/β-catenin pathway[J].Mol Cancer,2018,17(1):126.
[11]Li D,Yang M,Liao A,et al.Linc00483 as ceRNA regulates proliferation and apoptosis through activating MAPKs in gastric cancer[J].J Cell Mol Med,2018,22(8):3875-3886.
[12]Robinson MD,Mc Carthy DJ,Smyth GK.edgeR:a Bioconductor package for differential expression analysis of digital gene expression data[J].Bioinformatics,2010,26(1):139.
[13]Jeg gari A,Marks DS,Larsson E.miRcode:a map of putative microRNA target sites in the long non-coding transcriptome[J].Bioinformatics,2012,28(15):2062-2063.
[14]Hsu SD,Tseng YT,Shrestha S,et al.miRTar Base update 2014:an information resource for experimentally validated miRNA-target interactions[J].Nucleic Acids Res,2014,42:78-85.
[15]John B,Enright AJ,Aravin A,et al.Human MicroRNA targets[J].PLoS Biol,2004,2(11):e363.
[16]Park K,Kim KB.miRTar Hunter:a prediction system for identifying human microRNA target sites[J].Mol Cells,2013,35(3):195-201.
[17]Sh annon 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.
[18]Zhao Y,Liu Y,Lin L,et al.The lncRNA MACC1-AS1 promotes gastric cancer cell metabolic plasticity via AMPK/Lin28 mediated mRNA stability of MACC1[J].Mol Cancer,2018,17(1):69.
[19]Cao X,Xu J,Yue D.LncRNA-SNHG16 predicts poor prognosis and promotes tumor proliferation through epigenetically silencing p21 in bladder cancer[J].Cancer Gene Therapy,2017,25(1-2):1.
[20]Zhao Y,Wang H,Wu C,et al.Construction and investigation of lncRNA-associated ceRNA regulatory network in papillary thyroid cancer[J].Onco Rep,2018,39(3):1197-1206.
[21]Ghorbanmehr N,Gharbi S,AUID-Oho,et al.miR-21-5p,miR-141-3p,and miR-205-5p levels in urine-promising biomarkers for the identification of prostate and bladder cancer[J].Prostate,2018.
[22]Li L,Li S.miR-205-5p inhibits cell migration and invasion in prostatic carcinoma by targeting ZEB1[J].Oncol Lett,2018,16(2):1715-1721.
[23]Chu P,Liang A,Jiang A,et al.miR-205 regulates the proliferation and invasion of ovarian cancer cells via suppressing PTEN/SMAD4expression[J].Oncol Lett,2018,15(5):7571-7578.
[24]Su N,Qiu H,Chen Y,et al.miR-205 promotes tumor proliferation and invasion through targeting ESRRG in endometrial carcinoma[J].Oncol Rep,2013,29(6):2297-2302.
[25]Wu Z,Huang W,Wang X,et al.Circular RNA CEP128 acts as a sponge of miR-145-5p in promoting the bladder cancer progression via regulating SOX11[J].Mol Med,2018,24(1):40.
[26]Lu R,Ji Z,Li X,et al.miR-145 functions as tumor suppressor and targets two oncogenes,ANGPT2 and NEDD9,in renal cell carcinoma[J].J Cancer Res Clin Oncol,2014,140(3):387-397.
[27]Zhu N,Hou J,Wu Y,et al.Integrated analysis of a competing endogenous RNA network reveals key lncRNAs aspotential prognostic biomarkers for human bladder cancer[J].Medicine(Baltimore),2018,97(35):e11887.
[28]Di AS,Valenti F,Sacconi A,et al.Long Non-coding MIR205HGDepletes Hsa-miR-590-3p Leading to Unrestrained Proliferation in Head and Neck Squamous Cell Carcinoma[J].Theranostics,2018,8(7):1850-1868.
[29]贾业贵,许浪.YAP蛋白在不同恶性程度的胃癌组织中的表达及其死亡率的影响[J].热带医学杂志,2016,16(9):1174-1176.