基于数据挖掘分析ABAT基因在肝细胞癌中的表达及意义
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摘要
目的利用数据库分析基因ABAT在肝细胞癌中的表达以及意义。方法利用Oncomine数据库及GEPIA分析ABAT在肝细胞癌组织中的表达情况;利用GEPIA做ABAT mRNA与肝细胞癌患者生存期以及与病理分期程度的相关性分析;经MethHC数据库分析ABAT基因启动子区甲基化水平; String数据库分析与ABAT蛋白相互作用的蛋白网络;通过The Human Protein Atlas分析ABAT蛋白在肝细胞癌组织中的表达情况以及ABAT在蛋白水平上对患者预后的影响。结果 mRNA水平上,ABAT在肝细胞癌组织中较正常肝组织显著低表达,其mRNA水平低者预后较差(log-rank,P=0. 002 1),ABAT mRNA水平越低者病理分期恶性程度越高(P=0. 002 34)。ABAT蛋白在肝细胞癌组织中也较正常肝组织表达降低,蛋白表达水平低的患者预后较差(log-rank,P=2. 14×10-3)。肝细胞癌中ABAT基因启动子区甲基化水平较正常肝组织显著升高(P <0. 005)。与ABAT相互作用的蛋白有ALDH1A3、ALDH9A1、ALDH3A2、GAD1、GAD2等,可能参与细胞凋亡、氧化还原及神经递质分泌等细胞功能。结论通过肿瘤基因数据库信息挖掘发现,无论在mRNA水平或是蛋白水平上,ABAT在肝细胞癌组织中呈低表达,且与患者生存期有关。目前采用数据库挖掘分析数据可为临床上肝细胞癌的诊断以及预后评估提供参考,将为后续的肿瘤研究提供重要的理论依据。
Objective To investigate the expression and significance of the ABAT gene in hepatocellular carcinoma( HCC) using relateddatabases. Methods The Oncomine database and GEPIA were used to analyze the expression of ABAT in HCC tissue. GEPIA was used toinvestigate the correlation of ABAT mRNA with the survival time and pathological stage of HCC patients. The MethHC database was used toanalyze the methylation level of ABAT promoter region. The String database was used to analyze the network of proteins interacting withABAT protein. The Human Protein Atlas was used to analyze the expression of ABAT protein in HCC tissue and the influence of the proteinexpression of ABAT on prognosis. Results The mRNA expression of ABAT in HCC tissue was significantly lower than that in normal livertissue; patients with lower mRNA expression tended to have a poorer prognosis( log-rank,P = 0. 002 1) and a higher degree of malignancy( P = 0. 002 34). The protein expression of ABAT in HCC tissue was significantly lower than that in normal liver tissue,and patients withlower protein expression tended to have a poorer prognosis( log-rank,P = 2. 14 × 10-3). The methylation level of ABAT promoter region inHCC tissue was significantly higher than that in normal liver tissue( P < 0. 005). The proteins interacting with ABAT included ALDH1 A3,ALDH9 A1,ALDH3 A2,GAD1,and GAD2,which might be involved in cell functions such as cell apoptosis,redox,and neurotransmittersecretion. Conclusion Data mining of tumor gene databases shows that there are low levels of mRNA and protein expression of ABAT inHCC tissue,which is associated with patient's survival time. At present,database mining can provide a reference for the diagnosis andprognosis evaluation of HCC and a theoretical basis for tumor research in the future.
Objective To investigate the expression and significance of the ABAT gene in hepatocellular carcinoma( HCC) using relateddatabases. Methods The Oncomine database and GEPIA were used to analyze the expression of ABAT in HCC tissue. GEPIA was used toinvestigate the correlation of ABAT mRNA with the survival time and pathological stage of HCC patients. The MethHC database was used toanalyze the methylation level of ABAT promoter region. The String database was used to analyze the network of proteins interacting withABAT protein. The Human Protein Atlas was used to analyze the expression of ABAT protein in HCC tissue and the influence of the proteinexpression of ABAT on prognosis. Results The mRNA expression of ABAT in HCC tissue was significantly lower than that in normal livertissue; patients with lower mRNA expression tended to have a poorer prognosis( log-rank,P = 0. 002 1) and a higher degree of malignancy( P = 0. 002 34). The protein expression of ABAT in HCC tissue was significantly lower than that in normal liver tissue,and patients withlower protein expression tended to have a poorer prognosis( log-rank,P = 2. 14 × 10-3). The methylation level of ABAT promoter region inHCC tissue was significantly higher than that in normal liver tissue( P < 0. 005). The proteins interacting with ABAT included ALDH1 A3,ALDH9 A1,ALDH3 A2,GAD1,and GAD2,which might be involved in cell functions such as cell apoptosis,redox,and neurotransmittersecretion. Conclusion Data mining of tumor gene databases shows that there are low levels of mRNA and protein expression of ABAT inHCC tissue,which is associated with patient's survival time. At present,database mining can provide a reference for the diagnosis andprognosis evaluation of HCC and a theoretical basis for tumor research in the future.
引文
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[23] JANSEN MP,SAS L,SIEUWERTS AM,et al. Decreased ex-pression of ABAT and STC2 hallmarks ER-positive inflamma-tory breast cancer and endocrine therapy resistance in ad-vanced disease[J]. Mol Oncol,2015,9(6):1218-1233.
[24] AL-WADEI HA,ULLAH MF,AL-WADEI M. GABA(gamma-aminobutyric acid),a non-protein amino acid counters thebeta-adrenergic cascade-activated oncogenic signaling inpancreatic cancer:A review of experimental evidence[J].Mol Nutr Food Res,2011,55(12):1745-1758.
[25] TIAN H,WU JX,SHAN FX,et al. Gamma-aminobutyric acidinduces tumor cells apoptosis via GABABR1·beta-arrestins·JNKs signaling module[J]. Cell Biochem Biophys,2015,71(2):679-688.
[26] INADA T,KOGA M,ISHIGURO H,et al. Pathway-based as-sociation analysis of genome-wide screening data suggestthat genes associated with the gamma-aminobutyric acid re-ceptor signaling pathway are involved in neuroleptic-in-duced,treatment-resistant tardive dyskinesia[J]. Pharma-cogenet Genom,2008,18(4):317-323.
[27] LI X,ZHANG J,WU X,et al. Polymorphisms of ABAT,SCN2Aand ALDH5A1 may affect valproic acid responses in the treatmentof epilepsy in Chinese[J]. Pharmacogenomics,2016,17(18):2007-2014.
[28] PANOSYAN EH,LIN HJ,KOSTER J,et al. In search of drug-gable targets for GBM amino acid metabolism[J]. BMCCancer,2017,17(1):162.
[29] LI C,WANG Q,MA J,et al. Integrative pathway analysis ofgenes and metabolites reveals metabolism abnormal subpath-way regions and modules in esophageal squamous cell carci-noma[J]. Molecules,2017,22(10):1599.
[2] NAGAPPA M,BINDU PS,CHIPLUNKAR S,et al. Hypersomno-lence-hyperkinetic movement disorder in a child with compoundheterozygous mutation in 4-aminobutyrate aminotransferase(ABAT)gene[J]. Brain Dev,2017,39(2):161-165.
[3] ICHIKAWA K,TSUJI M,TSUYUSAKI Y,et al. Serial magneticresonance imaging and1H-magnetic resonance spectrosco-py in GABA transaminase deficiency:A case report[J]. JIMDRep,2019,43:7-12.
[4] BARNBY G,ABBOTT A,SYKES N,et al. Candidate-genescreening and association analysis at the autism-susceptibilitylocus on chromosome 16p:Evidence of association at GRIN2Aand ABAT[J]. Am J Hum Genet,2005,76(6):950-966.
[5] BESSE A,WU P,BRUNI F,et al. The GABA transaminase,ABAT,is essential for mitochondrial nucleoside metabolism[J]. Cell Metabolism,2015,21(3):417-427.
[6] BESSE A,PETERSEN AK,HUNTER JV,et al. Personalizedmedicine approach confirms a milder case of ABAT deficiency[J]. Mol Brain,2016,9(1):93.
[7] De BIASE D,BARRA D,SIMMACO M,et al. Primary structureand tissue distribution of human 4-aminobutyrate aminotrans-ferase[J]. Eur J Biochem,1995,227(1-2):476-480.
[8] BUDCZIES J,BROCKMLLER SF,MLLER BM,et al. Com-parative metabolomics of estrogen receptor positive and estro-gen receptor negative breast cancer:Alterations in glutamineand beta-alanine metabolism[J]. J Proteomics,2013,94:279-288.
[9] CHEN P,WANG F,FENG J,et al. Co-expression network a-nalysis identified six hub genes in association with metastasisrisk and prognosis in hepatocellular carcinoma[J]. Oncotar-get,2017,8(30):48948-48958.
[10] REIS H,PADDEN J,AHRENS M,et al. Differential proteomicand tissue expression analyses identify valuable diagnostic bi-omarkers of hepatocellular differentiation and hepatoid adeno-carcinomas[J]. Pathology,2015,47(6):543-550.
[11] TANG Z,LI C,KANG B,et al. GEPIA:A web server for cancerand normal gene expression profiling and interactive analyses[J]. Nucleic Acids Res,2017,45(W1):W98-W102.
[12] HUANG WY,HSU SD,HUANG HY,et al. Meth HC:A data-base of DNA methylation and gene expression in human canc-er[J]. Nucleic Acids Res,2015,43(Database issue):d856-d861.
[13] SZKLARCZYK D,MORRIS JH,COOK H,et al. The STRINGdatabase in 2017:Quality-controlled protein-protein associ-ation networks,made broadly accessible[J]. Nucleic AcidsRes,2017,45(D1):d362-d368.
[14] UHLEN M,OKSVOLD P,FAGERBERG L,et al. Towards aknowledge-based human protein atlas[J]. Nat Biotechnol,2010,28(12):1248-1250.
[15] UHLEN M,FAGERBERG L,HALLSTROM BM,et al. Proteomics.Tissue-based map of the human proteome[J]. Science,2015,347(6220):1260419.
[16] MAS VR,MALUF DG,ARCHER KJ,et al. Genes involved inviral carcinogenesis and tumor initiation in hepatitis C virus-in-duced hepatocellular carcinoma[J]. Mol Med,2009,15(3-4):85-94.
[17] ROESSLER S,JIA HL,BUDHU A,et al. A unique metastasisgene signature enables prediction of tumor relapse in early-stage hepatocellular carcinoma patients[J]. Cancer Res,2010,70(24):10202-10212.
[18] WURMBACH E,CHEN YB,KHITROV G,et al. Genome-widemolecular profiles of HCV-induced dysplasia and hepatocellularcarcinoma[J]. Hepatology,2007,45(4):938-947.
[19] WANG FS,FAN JG,ZHANG Z,et al. The global burden ofliver disease:The major impact of China[J]. Hepatology,2014,60(6):2099-2108.
[20] HAN K,KIM JH. Transarterial chemoembolization in hepato-cellular carcinoma treatment:Barcelona clinic liver cancerstaging system[J]. World J Gastroenterol,2015,21(36):10327-10335.
[21] CILLO U,VITALE A,GRIGOLETTO F,et al. Prospective vali-dation of the Barcelona clinic liver cancer staging system[J].J Hepatol,2006,44(4):723-731.
[22] BUDCZIES J,DENKERT C. Tissue-based metabolomics toanalyze the breast cancer metabolome[J]. Recent ResultsCancer Res,2016,207:157-175.
[23] JANSEN MP,SAS L,SIEUWERTS AM,et al. Decreased ex-pression of ABAT and STC2 hallmarks ER-positive inflamma-tory breast cancer and endocrine therapy resistance in ad-vanced disease[J]. Mol Oncol,2015,9(6):1218-1233.
[24] AL-WADEI HA,ULLAH MF,AL-WADEI M. GABA(gamma-aminobutyric acid),a non-protein amino acid counters thebeta-adrenergic cascade-activated oncogenic signaling inpancreatic cancer:A review of experimental evidence[J].Mol Nutr Food Res,2011,55(12):1745-1758.
[25] TIAN H,WU JX,SHAN FX,et al. Gamma-aminobutyric acidinduces tumor cells apoptosis via GABABR1·beta-arrestins·JNKs signaling module[J]. Cell Biochem Biophys,2015,71(2):679-688.
[26] INADA T,KOGA M,ISHIGURO H,et al. Pathway-based as-sociation analysis of genome-wide screening data suggestthat genes associated with the gamma-aminobutyric acid re-ceptor signaling pathway are involved in neuroleptic-in-duced,treatment-resistant tardive dyskinesia[J]. Pharma-cogenet Genom,2008,18(4):317-323.
[27] LI X,ZHANG J,WU X,et al. Polymorphisms of ABAT,SCN2Aand ALDH5A1 may affect valproic acid responses in the treatmentof epilepsy in Chinese[J]. Pharmacogenomics,2016,17(18):2007-2014.
[28] PANOSYAN EH,LIN HJ,KOSTER J,et al. In search of drug-gable targets for GBM amino acid metabolism[J]. BMCCancer,2017,17(1):162.
[29] LI C,WANG Q,MA J,et al. Integrative pathway analysis ofgenes and metabolites reveals metabolism abnormal subpath-way regions and modules in esophageal squamous cell carci-noma[J]. Molecules,2017,22(10):1599.