CIART在肝细胞癌组织中的表达及其临床意义
|
摘要
目的探讨昼夜相关转录抑制因子(CIART)在肝癌组织中的表达及其与肝癌患者临床特征和预后间的相关性。方法基于癌症基因组图集(TCGA)数据库与人类蛋白质图集(HPA)数据库,比较CIART在肝癌组织和正常肝组织中mRNA及蛋白水平的表达量;分析CIART mRNA表达量与肝癌患者临床特征及预后间的相关性;利用c Bio Portal在线平台分析CIART基因拷贝数变异及其启动子区DNA甲基化情况;采用基因集富集分析(GSEA)研究CIART基因表达水平与京都基因和基因组百科全书(KEGG)通路基因集的相关性。结果 CIART在肝癌组织中mRNA和蛋白水平表达量均较正常肝组织呈现上调,且CIART mRNA表达量对肝癌具有较好的诊断效能(AUC=0. 7794,P <0. 01)。除患者性别(P <0. 01)外,CIART mRNA表达量与肝癌患者其余临床病理特征间无显著关联(P均> 0. 05)。Kaplan-Meier分析及Cox回归分析提示,CIART mRNA高表达是影响肝癌患者总体生存率和无复发生存率的独立危险因素(P均<0. 05)。370例肝癌患者中有42例(11. 35%)存在CIART基因扩增变异,且与CIART mRNA上调显著相关(P <0. 05)。此外,370例肝癌患者CIART启动子区DNA甲基化程度与CIART mRNA表达量呈显著负相关(Pearson's r=-0. 7126,P <0. 01)。GSEA分析显示,高表达CIART样本中存在基础转录因子(BASAL_TRANSSCRIPTION_FACTORS)通路和碱基切除修复(BASE_EXCISION_REPAIR)通路基因集的富集(P均<0. 05)。结论 CIART可能作为一种癌基因参与肝细胞癌的发生、发展,并具有成为肝细胞癌诊断标志物、预后指标及治疗靶点的潜在价值。
Objective To investigate the expression of circadian associated repressor of transcription( CIART) in hepatocellular carcinoma( HCC) tissues and its association with clinical features and prognosis in HCC patients. Methods Based on the databases of Cancer Genome Atlas( TCGA) and Human Protein Atlas( HPA),the expression levels of CIART mRNA and protein in HCC tissues and normal liver tissues were compared,and the correlation of CIART mRNA expression levels with the clinicopathologic characteristics and prognosis of the patients were analyzed. CIART gene copynumber alterations and DNA methylation in its promoter region were analyzed by c Bio Portal online platform. The correlation between CIART expression level and Kyoto Encyclopedia of Genes and Genomes( KEGG) pathway gene set was investigated by gene set enrichment analysis( GSEA). Results The expression levels of CIART mRNA and protein in HCC tissues were up-regulated compared with normal liver tissues,and the expression level of CIART mRNA had better diagnostic efficiency for liver cancer( AUC = 0. 7794,P < 0. 01). Except for patients' gender( P < 0. 01),there was no significant relationship between CIART mRNA expression level and other clinicopathological features( all P > 0. 05).Kaplan-Meier analysis and Cox regression analysis prompted that CIART mRNA high-expression was the independent risk factor influencing overall survival rate and recurrence-free survival rate of HCC patients( all P < 0. 05). There were amplification variants of CIART gene in 42( 11. 35%) of 370 patients with HCC,and the variants were significantly correlated with up-regulation of CIART mRNA expression( P < 0. 05). In addition,the degree of CIART DNA methylation in its promoter region was significantly negatively correlated with CIART mRNA level in 370 HCC patients( Pearson's r =-0. 7126,P < 0. 01). GSEA analysis showed that there were gene set enrichments of basal transcription factor( BASAL_TRANSSCRIPTION_FACTORS) pathway and base excision repair( BASE_EXCISION_REPAIR) pathway in samples of CIART high-expression( all P < 0. 05). Conclusions CIART served as a kind of oncogene may be involved in the occurrence and development of HCC,and it has a potential value for serving as HCC diagnostic marker,prognostic indicator and therapeutic target.
Objective To investigate the expression of circadian associated repressor of transcription( CIART) in hepatocellular carcinoma( HCC) tissues and its association with clinical features and prognosis in HCC patients. Methods Based on the databases of Cancer Genome Atlas( TCGA) and Human Protein Atlas( HPA),the expression levels of CIART mRNA and protein in HCC tissues and normal liver tissues were compared,and the correlation of CIART mRNA expression levels with the clinicopathologic characteristics and prognosis of the patients were analyzed. CIART gene copynumber alterations and DNA methylation in its promoter region were analyzed by c Bio Portal online platform. The correlation between CIART expression level and Kyoto Encyclopedia of Genes and Genomes( KEGG) pathway gene set was investigated by gene set enrichment analysis( GSEA). Results The expression levels of CIART mRNA and protein in HCC tissues were up-regulated compared with normal liver tissues,and the expression level of CIART mRNA had better diagnostic efficiency for liver cancer( AUC = 0. 7794,P < 0. 01). Except for patients' gender( P < 0. 01),there was no significant relationship between CIART mRNA expression level and other clinicopathological features( all P > 0. 05).Kaplan-Meier analysis and Cox regression analysis prompted that CIART mRNA high-expression was the independent risk factor influencing overall survival rate and recurrence-free survival rate of HCC patients( all P < 0. 05). There were amplification variants of CIART gene in 42( 11. 35%) of 370 patients with HCC,and the variants were significantly correlated with up-regulation of CIART mRNA expression( P < 0. 05). In addition,the degree of CIART DNA methylation in its promoter region was significantly negatively correlated with CIART mRNA level in 370 HCC patients( Pearson's r =-0. 7126,P < 0. 01). GSEA analysis showed that there were gene set enrichments of basal transcription factor( BASAL_TRANSSCRIPTION_FACTORS) pathway and base excision repair( BASE_EXCISION_REPAIR) pathway in samples of CIART high-expression( all P < 0. 05). Conclusions CIART served as a kind of oncogene may be involved in the occurrence and development of HCC,and it has a potential value for serving as HCC diagnostic marker,prognostic indicator and therapeutic target.
引文
[1] Tang A,Hallouch O,Chernyak V,et al. Epidemiology of hepatocellular carcinoma:target population for surveillance and diagnosis[J].Abdom Radiol(NY),2018,43(1):13-25.
[2] Plikus MV,Van Spyk EN,Pham K,et al. The circadian clock in skin:implications for adult stem cells,tissue regeneration,cancer,aging,and immunity[J]. J Biol Rhythms,2015,30(3):163-182.
[3] Shostak A. Circadian Clock,cell division,and cancer:from molecules to organism[J]. Int J Mol Sci,2017,18(4):873.
[4] Anafi RC,Lee Y,Sato TK,et al. Machine learning helps identify CHRONO as a circadian clock component[J]. PLo S Biol,2014,12(4):e1001840.
[5] Annayev Y,Adar S,Chiou YY,et al. Gene model 129(Gm129)encodes a novel transcriptional repressor that modulates circadian gene expression[J]. J Biol Chem,2014,289(8):5013-5024.
[6] Goriki A,Hatanaka F,Myung J,et al. A novel protein,CHRONO,functions as a core component of the mammalian circadian clock[J]. PLo S Biol,2014,12(4):e1001839.
[7] Li Y,Rong G,Kang H. Taxotere-induced elevated expression of IL8in carcinoma-associated fibroblasts of breast invasive ductal cancer[J]. Oncol Lett,2017,13(3):1856-1860.
[8] Tang Z,Li C,Kang B,et al. GEPIA:a web server for cancer and normal gene expression profiling and interactive analyses[J]. Nucleic Acids Res,2017,45(W1):W98-W102.
[9] Uhlen M,Oksvold P,Fagerberg L,et al. Towards a knowledge-based Human Protein Atlas[J]. Nat Biotechnol,2010,28(12):1248-1250.
[10] 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):139-140.
[11] Cerami E,Gao J,Dogrusoz U,et al. The c Bio cancer genomics portal:an open platform for exploring multidimensional cancer genomics data[J]. Cancer Discov,2012,2(5):401-404.
[12] Su C. Survivin in survival of hepatocellular carcinoma[J]. Cancer Lett,2016,379(2):184-190.
[13] Sánchez DI,González-Fernández B,Crespo I,et al. Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamineinduced hepatocellular carcinoma[J]. J Pineal Res,2018,65(3):e12506.
[14] Robinson R. Chronos:stress makes the clock tick[J]. PLo S Biol,2014,12(4):e1001838.
[15] Cardoso TF,Quintanilla R,Tibau J,et al. Nutrient supply affects the mRNA expression profile of the porcine skeletal muscle[J]. BMC Genomics,2017,18(1):603.
[16] Orozco-Solis R,Montellier E,Aguilar-Arnal L,et al. A circadian genomic signature common to ketamine and sleep deprivation in the anterior cingulate cortex[J]. Biol Psychiatry,2017,82(5):351-360.
[17] Felicio PS,Bidinotto LT,Melendez ME,et al. Genetic alterations detected by comparative genomic hybridization in BRCAX breast and ovarian cancers of Brazilian population[J]. Oncotarget,2018,9(44):27525-27534.
[18]张世光,宋文芹,杜智,等.肝细胞癌组织相关拷贝数扩增区域的鉴定[J].中华肿瘤杂志,2009,31(8):566-570.
[19] Eden A,Gaudet F,Waghmare A,et al. Chromosomal instability and tumors promoted by DNA hypomethylation[J]. Science,2003,300(5618):455.
[20] Zhou X,Zheng R,Zhang H,et al. Pathway crosstalk analysis of microarray gene expression profile in human hepatocellular carcinoma[J]. Pathol Oncol Res,2015,21(3):563-569.
[21] Yuan T,Wei J,Luo J,et al. Polymorphisms of base-excision repair genes hOGG1 326cys and XRCC1 280His increase hepatocellular carcinoma risk[J]. Dig Dis Sci,2012,57(9):2451-2457.
[2] Plikus MV,Van Spyk EN,Pham K,et al. The circadian clock in skin:implications for adult stem cells,tissue regeneration,cancer,aging,and immunity[J]. J Biol Rhythms,2015,30(3):163-182.
[3] Shostak A. Circadian Clock,cell division,and cancer:from molecules to organism[J]. Int J Mol Sci,2017,18(4):873.
[4] Anafi RC,Lee Y,Sato TK,et al. Machine learning helps identify CHRONO as a circadian clock component[J]. PLo S Biol,2014,12(4):e1001840.
[5] Annayev Y,Adar S,Chiou YY,et al. Gene model 129(Gm129)encodes a novel transcriptional repressor that modulates circadian gene expression[J]. J Biol Chem,2014,289(8):5013-5024.
[6] Goriki A,Hatanaka F,Myung J,et al. A novel protein,CHRONO,functions as a core component of the mammalian circadian clock[J]. PLo S Biol,2014,12(4):e1001839.
[7] Li Y,Rong G,Kang H. Taxotere-induced elevated expression of IL8in carcinoma-associated fibroblasts of breast invasive ductal cancer[J]. Oncol Lett,2017,13(3):1856-1860.
[8] Tang Z,Li C,Kang B,et al. GEPIA:a web server for cancer and normal gene expression profiling and interactive analyses[J]. Nucleic Acids Res,2017,45(W1):W98-W102.
[9] Uhlen M,Oksvold P,Fagerberg L,et al. Towards a knowledge-based Human Protein Atlas[J]. Nat Biotechnol,2010,28(12):1248-1250.
[10] 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):139-140.
[11] Cerami E,Gao J,Dogrusoz U,et al. The c Bio cancer genomics portal:an open platform for exploring multidimensional cancer genomics data[J]. Cancer Discov,2012,2(5):401-404.
[12] Su C. Survivin in survival of hepatocellular carcinoma[J]. Cancer Lett,2016,379(2):184-190.
[13] Sánchez DI,González-Fernández B,Crespo I,et al. Melatonin modulates dysregulated circadian clocks in mice with diethylnitrosamineinduced hepatocellular carcinoma[J]. J Pineal Res,2018,65(3):e12506.
[14] Robinson R. Chronos:stress makes the clock tick[J]. PLo S Biol,2014,12(4):e1001838.
[15] Cardoso TF,Quintanilla R,Tibau J,et al. Nutrient supply affects the mRNA expression profile of the porcine skeletal muscle[J]. BMC Genomics,2017,18(1):603.
[16] Orozco-Solis R,Montellier E,Aguilar-Arnal L,et al. A circadian genomic signature common to ketamine and sleep deprivation in the anterior cingulate cortex[J]. Biol Psychiatry,2017,82(5):351-360.
[17] Felicio PS,Bidinotto LT,Melendez ME,et al. Genetic alterations detected by comparative genomic hybridization in BRCAX breast and ovarian cancers of Brazilian population[J]. Oncotarget,2018,9(44):27525-27534.
[18]张世光,宋文芹,杜智,等.肝细胞癌组织相关拷贝数扩增区域的鉴定[J].中华肿瘤杂志,2009,31(8):566-570.
[19] Eden A,Gaudet F,Waghmare A,et al. Chromosomal instability and tumors promoted by DNA hypomethylation[J]. Science,2003,300(5618):455.
[20] Zhou X,Zheng R,Zhang H,et al. Pathway crosstalk analysis of microarray gene expression profile in human hepatocellular carcinoma[J]. Pathol Oncol Res,2015,21(3):563-569.
[21] Yuan T,Wei J,Luo J,et al. Polymorphisms of base-excision repair genes hOGG1 326cys and XRCC1 280His increase hepatocellular carcinoma risk[J]. Dig Dis Sci,2012,57(9):2451-2457.