胃癌中EXD3基因的表达及功能的生物信息学分析
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摘要
目的通过生物信息学分析研究胃癌与正常胃粘膜间具有差异性表达的基因,找出参与胃癌发生发展及预后的关键基因,并对其所涉及的功能进行分析预测。方法从GEO表达谱数据库中下载表达谱基因芯片数据GSE100935(包括18例胃癌样本及正常胃粘膜组织),利用Morpheus在线软件分析基因芯片GSE100935的数据,获得在胃癌与正常胃粘膜组织中存在差异表达的基因,并构建聚类分析热图;利用软件UALCAN在线分析差异表达基因在胃癌与正常胃粘膜组织中表达水平;利用Kaplan-Meier绘图软件对差异表达基因在胃癌患者中的表达高低进行生存分析;最后采用Fun Rich软件进行GO功能富集分析,网站STRING构建目的基因蛋白互作网络。结果通过分析基因芯片GSE100935获得45119个差异表达的基因;在线分析软件UALCAN显示EXD3基因在胃癌组织中高表达;同时生存分析提示当EXD3基因高表达时,胃癌患者的预后相对较差;GO功能富集分析发现,差异表达基因主要与胃癌细胞核苷酸的新陈代谢调节以及转录因子的活动有关。结论 EXD3可能是胃癌中潜在的癌基因,可能与DNA损伤修复有关,其表达上调在胃癌的发生发展及预后过程发挥重要作用,并有望成为判断胃癌患者预后的重要的生物学指标。
Objective To investigate the differentially expressed genes between gastric cancer and normal gastric mucosa by bioinformatics analysis,identify the important gene participating in the occurrence and progression of gastric cancer,and predict the functions of these genes.Methods The gene expression microarray data GSE100935(including 18 gastric cancer samples and normal gastric mucosal tissues) downloaded from the GEO expression profile database were analyzed using Morpheus to obtain the differentially expressed genes in gastric cancer,and a cluster analysis heat map was constructed.The online database UALCAN was used to obtain the expression levels of these differentially expressed genes in gastric cancer and normal gastric mucosa.The prognostic value of the differentially expressed genes in gastric cancer was evaluated with KaplanMeier survival analysis.GO functional enrichment analysis was performed using Fun-Rich software,and the STRING database was exploited to establish a PPI network for the differentially expressed genes.Results A total of 45119 differentially expressed genes were identified from GSE100935 microarray data.Analysis with UALCAN showed an obvious high expression of EXD3 gene in gastric cancer,and survival analysis suggested that a high expression level of EXD3 was associated with a poorer prognosis of the patients with gastric cancer.GO functional enrichment analysis found that the differentially expressed genes in gastric cancer were involved mainly in the regulation of nucleotide metabolism and the activity of transcription factors in the cancer cells.Conclusion EXD3 may be a potential oncogene in gastric cancer possibly in relation to DNA damage repair.The up-regulation of EXD3 plays an important role in the development and prognosis of gastric cancer,and may serve as an important indicator for prognostic evaluation of the patients.
Objective To investigate the differentially expressed genes between gastric cancer and normal gastric mucosa by bioinformatics analysis,identify the important gene participating in the occurrence and progression of gastric cancer,and predict the functions of these genes.Methods The gene expression microarray data GSE100935(including 18 gastric cancer samples and normal gastric mucosal tissues) downloaded from the GEO expression profile database were analyzed using Morpheus to obtain the differentially expressed genes in gastric cancer,and a cluster analysis heat map was constructed.The online database UALCAN was used to obtain the expression levels of these differentially expressed genes in gastric cancer and normal gastric mucosa.The prognostic value of the differentially expressed genes in gastric cancer was evaluated with KaplanMeier survival analysis.GO functional enrichment analysis was performed using Fun-Rich software,and the STRING database was exploited to establish a PPI network for the differentially expressed genes.Results A total of 45119 differentially expressed genes were identified from GSE100935 microarray data.Analysis with UALCAN showed an obvious high expression of EXD3 gene in gastric cancer,and survival analysis suggested that a high expression level of EXD3 was associated with a poorer prognosis of the patients with gastric cancer.GO functional enrichment analysis found that the differentially expressed genes in gastric cancer were involved mainly in the regulation of nucleotide metabolism and the activity of transcription factors in the cancer cells.Conclusion EXD3 may be a potential oncogene in gastric cancer possibly in relation to DNA damage repair.The up-regulation of EXD3 plays an important role in the development and prognosis of gastric cancer,and may serve as an important indicator for prognostic evaluation of the patients.
引文
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[37]Bagchi S,Raychaudhuri P.Damaged-DNA binding protein-2 drives apoptosis following DNA damage[J],Cell Div,2010,5(1):3.
[38]Barbieux C,Bacharouche J,Soussen C,et al.DDB2(damagedDNA binding 2)protein:a new modulator of nanomechanical properties and cell adhesion of breast cancer cells[J].Nanoscale,2016,8(9):5268-79.
[39]Cui TT,Srivastava AK,Han CH,et al.DDB2 represses ovarian cancer cell dedifferentiation by suppressing ALDH1A1[J].Cell Death Dis,2018,9(5):561-82.
[40]Barakat BM,Wang QE,Han CH,et al.Overexpression of DDB2enhances the sensitivity of human ovarian cancer cells to cisplatin by augmenting cellular apoptosis[J].Int J Cancer,2010,127(4):977-88.
[2]Aoyama T,Huctchins G,Arai T,et al.Identification of a high-risk subtype of intestinal-type Japanese gastric Cancer by quantitative measurement of the luminal tumor proportion[J].Cancer Med,2018,7(10):4914-23.
[3]Arco DD,Estrada ML,Molina RE,et al.Immunohistochemical classification of gastric cancer based on new molecular biomarkers:a potential predictor of survival[J].Virchows Arch,2018,473(6):687-95.
[4]Gao Y,Qi WW,Sun LB,et al.FOXO3 inhibits human gastric adenocarcinoma(AGS)cell growth by promoting autophagy in an acidic microenvironment[J].Cell Physiol Biochem,2018,49(1):335-48.
[5]Hao L,Leng J,Xiao RJ,et al.Bioinformatics analysis of the prognostic value of Tripartite Motif 28 in breast cancer[J].Oncol Lett,2017,13(4):2670-8.
[6]von Mering C,Huynen M,Jaeggi D,et al.STRING:a database of predicted functional associations between proteins[J].Nucleic Acids Res,2003,31(1):258-61.
[7]Shen XB,Li PF,Xu YC,et al.Association of sirtuins with clinicopathological parameters and overall survival in gastric cancer[J].Oncotarget,2017,8(43):74359-70.
[8]He XX,Xie BS.Autophagy inhibition enhanced 5FUinduced cell death in human gastric carcinoma BGC823 cells[J].Mol Med Rep,2018,17(5):6768-76.
[9]Zhou JM,Wu A,Yu XT,et al.SIRT6 inhibits growth of gastric cancer by inhibiting JAK2/STAT3 pathway[J].Oncol Rep,2017,38(2):1059-66.
[10]Liu JW,He CY,Sun LP,et al.The DNA repair gene ERCC6rs1917799 polymorphism is associated with gastric cancer risk in Chinese[J].Asian Pac J Cancer Prev,2013,14(10):6103-8.
[11]Jing JJ,Lu YZ,Sun LP,et al.Epistatic SNP interaction of ERCC6with ERCC8 and their joint protein expression contribute to gastric cancer/atrophic gastritis risk[J].Oncotarget,2017,8(26):43140-52.
[12]Xu Q,Liu JW,He CY,et al.The interaction effects of pri-let-7a-1rs10739971 with PGC and ERCC6 gene polymorphisms in gastric cancer and atrophic gastritis[J].PLoS One,2014,9(2):e89203.
[13]Liu JW,Deng N,Xu Q,et al.Polymorphisms of multiple genes involved in NER pathway predict prognosis of gastric cancer[J].Oncotarget,2016,7(30):48130-42.
[14]Matsutani,N.Expression of MRE11 complex(MRE11,RAD50,NBS1)and hRap1 and its relation with telomere regulation,telomerase activity in human gastric carcinomas[J].Pathobiology,2001,69(4):219-24.
[15]Altan B,Yokobori T,Ide M,et al.High expression of MRE11-RAD50-NBS1 is associated with poor prognosis and chemoresistance in gastric cancer[J].Anticancer Res,2016,36(10):5237-47.
[16]Wang KX,Chen D.Flap endonuclease 1 is a promising candidate biomarker in gastric cancer and is involved in cell proliferation and apoptosis[J].Int J Mol Med,2014,33(5):1268-74.
[17]Lazar DC,Avram MF,Romoan IA,et al.Prognostic significance of tumor immune microenvironment and immunotherapy:Novel insights and future perspectives in gastric cancer[J].World JGastroenterol,2018,24(32):3583-616.
[18]Asadi-Lari MH,Esmaeili-Hesari A.Changes in health-related quality of Life in oesophagogastric cancer patients participating in palliative and curative therapies[J],2018,32(4):31-2.
[19]Che,Y.Helicobacter pylori-induced exosomal Met educates tumourassociated macrophages to promote gastric cancer progression[J],2018,22(11):5708-19.
[20]欧玉荣,康敏,周蕾,等.胃癌中幽门螺杆菌L型感染与MIF、MMP9、VEGF表达的关系[J].南方医科大学学报,2014,34(2):180-7.
[21]Garcia-Rua V,Feijoo-Bandin S,Garcia-Vence M,et al.Metabolic alterations derived from absence of Two-Pore Channel 1 at cardiac level[J].J Biosci,2016,41(4):643-58.
[22]Arndt L,Castonguay J,Arlt E,et al.NAADP and the two-pore channel protein 1 participate in the acrosome reaction in mammalian spermatozoa[J].Mol Biol Cell,2014,25(6):948-64.
[23]Patel SC,E Brailoiu N.(2+)signals through two-pore channel-1require arginine residues in the first S4-S5 linker[J],Cell Calcium,2017,68(12):1-4.
[24]Horton JS,Wakano CT,Speck M,et al.Two-pore Channel 1interacts with citron kinase,regulating completion of cytokinesis[J].Channels(Austin),2015,9(1):21-9.
[25]Auburger,G.12q24 locus association with type 1 diabetes:SH2B3or ATXN2[J]?World J Diabetes,2014,5(3):316-27.
[26]Borghero G,Pugliatti M,Marrosu FA,et al.ATXN2 is a modifier of phenotype in ALS patients of Sardinian ancestry[J].Neurobiol Aging,2015,36(10):e1-5.
[27]Ding,D.ATXN2 polymorphism modulates age at onset in Machado-Joseph disease[J].Brain,2016,139(10):e59.
[28]Chio A,Calvo A,Moglia C,et al.ATXN2 polyQ intermediate repeats are a modifier of ALS survival[J].Neurology,2015,84(3):251-8.
[29]Alekseev S,Kool H,Rebel H,et al.Enhanced DDB2 expression protects mice from carcinogenic effects of chronic UV-B irradiation[J].Cancer Res,2005,65(22):10298-306.
[30]Almaguer-Mederos LE,Aguilera-Rodriguez RA,Almaguer-Gotay D,et al.Normal ATXN2 alleles influences on the age at onset in spinocerebellar ataxia type 2[J].Mov Disord,2017,32(9):1329-30.
[31]Fang,Z.Association of endothelin-1 gene polymorphisms with essential hypertension in a Chinese population[J].Genet Mol Res,2017,16(3):gmr16037446.
[32]Becraft PW.Cell fate specification in the cereal endosperm[J].Semin Cell Dev Biol,2001,12(5):387-94.
[33]Suzuki A,Niimi Y,Shinmyozu K,et al.Dead end1 is an essential partner of NANOS2 for selective binding of target RNAs in male germ cell development[J].EMBO Rep,2016,17(1):37-46.
[34]Li M,Lopato S,Hrmova M,et al.Expression patterns and protein structure of a lipid transfer protein END1 from Arabidopsis[J].Planta,2014,240(6):1319-34.
[35]Altmae S,Reimand J,Hovatta O,et al.Research resource:interactome of human embryo implantation:identification of gene expression pathways,regulation,and integrated regulatory networks[J].Mol Endocrinol,2012,26(1):203-17.
[36]Alekseev,S.Cellular concentrations of DDB2 regulate dynamic binding of DDB1 at UV-induced DNA damage[J].Mol Cell Biol,2008,28(24):7402-13.
[37]Bagchi S,Raychaudhuri P.Damaged-DNA binding protein-2 drives apoptosis following DNA damage[J],Cell Div,2010,5(1):3.
[38]Barbieux C,Bacharouche J,Soussen C,et al.DDB2(damagedDNA binding 2)protein:a new modulator of nanomechanical properties and cell adhesion of breast cancer cells[J].Nanoscale,2016,8(9):5268-79.
[39]Cui TT,Srivastava AK,Han CH,et al.DDB2 represses ovarian cancer cell dedifferentiation by suppressing ALDH1A1[J].Cell Death Dis,2018,9(5):561-82.
[40]Barakat BM,Wang QE,Han CH,et al.Overexpression of DDB2enhances the sensitivity of human ovarian cancer cells to cisplatin by augmenting cellular apoptosis[J].Int J Cancer,2010,127(4):977-88.