FU Huijia,WANG Menghao,LIU Xiru.Bioinformatics analysis of differentially expressed genes in endometrium with recurrent implantation failure[J].J Third Mil Med Univ,2019,41(13):1246-1252.

反复着床失败子宫内膜组织差异表达基因的生物信息学分析(/HTML )




Bioinformatics analysis of differentially expressed genes in endometrium with recurrent implantation failure
400016 重庆,重庆医科大学附属第一医院生殖医学中心1;400010 重庆,重庆医科大学附属第二医院肝胆外科2
FU Huijia1 WANG Menghao2 LIU Xiru1  

1Center for Reproductive Medicine, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016; 2Department of Hepatobiliary Surgery, the Second Affiliated Hospital of Chongqing Medical University, Chongqing, 400010, China

recurrent implantation failure endometrium bioinformatics gene
R318.04; R394.3; R711.6

目的应用生物信息学方法分析体外受精(in vitro fertilization,IVF)后反复着床失败(recurrent implantation failure,RIF)的相关基因,以探讨反复着床失败的发病机制。方法从美国国立生物技术信息中心(National Center for Biotechnology Information, NCBI)公共数据平台(Gene Expression Omnibus,GEO)下载基因芯片数据集GSE111974,使用R语言筛选出反复着床失败和正常生育女性子宫内膜组织的差异表达基因(differentiallyexpressed genes, DEGs)。再利用生物信息学分析工具DAVID(The database forannotation,visualization and integrated discovery)对差异基因进行基因本体论(Gene Ontology,GO)功能富集分析和京都基因和基因组百科全书(Kyoto encyclopedia of genes and genomes, KEGG)通路分析,利用STRING(Search Tool for the Retrieval of Interacting Genes)在线数据库和Cytoscape软件进行蛋白互作网络分析。结果初筛出170个明显差异表达的基因,其中上调者127个,下调者43个。GO功能富集显示:这些DEGs主要富集于细胞膜、内质网等区域,主要参与氧化还原过程、细胞周期阻滞、脂质代谢过程等;主要与血红素结合、信号传递器活性、维甲酸结合、过氧化物酶活性等功能簇相关。KEGG分析显示其主要参与代谢途径信号通路、催产素信号通路、肿瘤坏死因子信号通路等。STRING在线数据库和Cytoscape软件分析发现PTGS2、TOP2A、ACTA2等为反复着床失败的关键基因。结论采用生物信息学方法筛选出RIF患者子宫内膜组织差异表达的关键基因有PTGS2、TOP2A、ACTA2等,可能在RIF的发病机制中起重要作用。


ObjectiveTo investigate the related genes in the endometrium with recurrent implantation failure (RIF) after in vitro fertilization (IVF) by bioinformatics analysis in order to illustrate the underlying pathogenesis of RIF. MethodsThe dataset GSE111974 was downloaded from Gene Expression Omnibus (GEO) in National Center for Biotechnology Information (NCBI). R/Bioconductor packages “marray” and “limma” were applied to this model to screen out the differentially expressed gene (DEGs) in the patients with RIF compared with normal fertile controls. Then, the database for annotation, visualization and integrated discovery (DAVID) was employed to make Gene Ontology (GO) analysis and Kyoto encyclopedia of genes and genomes (KEGG) pathway analysis to analyze the protein-protein interaction network by the Search Tool for the Retrieval of Interacting Genes (STRING) online database and Cytoscape software. ResultsThere were 170 DEGs turning out, of which 127 genes were up-regulated and 43 were down-regulated. GO analysis shows that the DEGs mainly concentrate in cell membrane, endoplasmic reticulum and other areas, which primarily participate in oxidation-reduction process, cell cycle arrest and lipid metabolic process, etc. Their molecular functions are involved in heme binding, signal transducer activity, retinoic acid binding and peroxidase activity. KEGG pathway analysis showed that these genes are mainly involved in metabolic pathways, oxytocin signaling pathway, and TNF signaling pathway, etc. STRING online database and Cytoscape software found out that DEGs PTGS2, TOP2A and ACTA2 were the hub genes of RIF. ConclusionThe key genes PTGS2, TOP2A and ACTA2 and transcription factors CEBPB, CDX2 and ESR1 may play important role in the pathogenesis of RIF.


[1]TALAULIKAR V S, ARULKUMARAN S. Reproductive outcomes after assisted conception[J]. Obstet  Gynecol Surv, 2012, 67(9): 566-583. DOI:10.1097/ogx.0b013e31826 a5d4a.
[2]THORNHILL A R, DEDIE-SMULDERS C E, GERAEDTS J P, et al. ESHRE PGD Consortium ‘Best practice guidelines for clinical preimplantation genetic diagnosis (PGD) and preimplantation genetic screening (PGS)’[J]. Hum Reprod, 2005, 20(1): 35-48. DOI:10. 1093/humrep/deh579.
[3]SIMON A, LAUFER N. Repeated implantation failure: clinical approach[J]. Fertil Steril, 2012, 97(5): 1039-1043. DOI:10.1016/j.fertnstert.2012. 03.010.
[4]JANKY R, VERFAILLIE A, IMRICHOV H, et al. IRegulon: from a gene list to a gene regulatory network using large motif and track collections[J]. PLoS Comput Biol, 2014, 10(7): e1003731. DOI:10.1371/journal.pcbi.1003731.
[5]MARTINI A E, JASULAITIS S, FOGG L F, et al. Evaluating the utility of intralipid infusion to improve live birth rates in patients with recurrent pregnancy loss or recurrent implantation failure[J]. J Hum Reprod Sci, 2018, 11(3): 261-268. DOI:10.4103/jhrs.JHRS_28_18.
[6]LEE S, LEE J W, LEE S K. UTX, a histone H3-lysine 27 demethylase, acts as a critical switch to activate the cardiac developmental program[J]. Dev Cell, 2012, 22(1): 25-37. DOI:10.1016/j.devcel.2011.11.009.
[7]ZHU Z Q, WANG Y R, LI X, et al. PHF8 is a histone H3K9me2 demethylase regulating rRNA synthesis[J]. Cell Res, 2010, 20(7): 794-801. DOI:10.1038/cr.2010.75.
[8]GU L D, HITZEL J, MOLL F, et al. The histone demethylase PHF8 is essential for endothelial cell migration[J]. PLoS ONE, 2016, 11(1): e0146645. DOI:10.1371/journal.pone.0146645.
[9]XIANG Y Z, LI F, WANG L, et al. Decreased calpain 6 expression is associated with tumorigenesis and poor prognosis in HNSCC[J]. Oncol Lett, 2017, 13(4): 2237-2243. DOI:10.3892/ol.2017.5687.
[10]ANDRIQUE C, MORARDET L, LINARES L K, et al. Calpain-6 controls the fate of sarcoma stem cells by promoting autophagy and preventing senescence[J]. JCI Insight, 2018, 3(17): 121225. DOI:10.1172/jci.insight.121225.
[11]KIM H, ABD ELMAGEED Z Y, JU J H, et al. PDZK1 is a novel factor in breast cancer that is indirectly regulated by estrogen through IGF-1R and promotes estrogen-mediated growth[J]. Mol Med, 2013, 19: 253-262. DOI:10.2119/molmed. 2011.00001.
[12]KUBUSHIRO K, KOJIMA K, MIKAMI M, et al. Menstrual cycle-associated alteration of sulfogalactosylceramide in human uterine endometrium: possible induction of glycolipid sulfation by sex steroid hormones[J]. Arch Biochem Biophys, 1989, 268(1): 129-136.
[13]ZHU Z, DENG H, FENDERSON B A, et al. Glycosphingolipids of human myometrium and endometrium and their changes during the menstrual cycle, pregnancy and ageing[J]. J Reprod Fertil, 1990, 88(1): 71-79.
[14]NAKAMURA H, HOSONO T, TANIGUCHI T, et al. Prediction of pregnancy after frozen-thawed embryo transfer via in vivo intrauterine oxidation-reduction potential measurements: A pilot study[J]. Reprod Med Biol, 2018, 17(3): 255-261. DOI:10.1002/rmb2. 12098.
[15]TSAI J H, CHI M M, SCHULTE M B, et al. The fatty acid beta-oxidation pathway is important for decidualization of endometrial stromal cells in both humans and mice[J]. Biol Reprod, 2014, 90(2): 34. DOI:10.1095/biolreprod.113.113217.
[16]VOGEL L K, SB M, HYER H, et al. Intestinal PTGS2 mRNA levels, PTGS2 gene polymorphisms, and colorectal carcinogenesis[J]. PLoS ONE, 2014, 9(8): e105254. DOI:10.1371/journal.pone.0105254.
[17]FRITZ P, CABRERA C M, DIPPON J, et al. C-ErbB2 and topoisomerase IIalpha protein expression independently predict poor survival in primary human breast cancer: A retrospective study[J]. Breast Cancer Res, 2005, 7(3): R374-R384. DOI:10.1186/bcr1012.
[18]JEON M, YOU D, BAE S Y, et al. Dimerization of EGFR and HER2 induces breast cancer cell motility through STAT1-dependent ACTA2 induction[J]. Oncotarget, 2017, 8(31): 50570- 50581. DOI:10.18632/oncotarget.10843.
[19]RAHADIANI N, IKEDA J, MAMAT S, et al. Expression of aldehyde dehydrogenase 1 (ALDH1) in endometrioid adenocarcinoma and its clinical implications[J]. Cancer Sci, 2011, 102(4): 903-908. DOI:10.1111/j.1349-7006.2011. 01864.x.
[20]WU F R, CHEN X Y, LIU Y Y, et al. Decreased MUC1 in endometrium is an independent receptivity marker in recurrent implantation failure during implantation window[J]. Reprod Biol Endocrinol, 2018, 16(1): 60. DOI:10.1186/s12958-018-0379-1.
[21]ZHU H Y, GE T X, PAN Y B, et al. Advanced role of hippo signaling in endometrial fibrosis: implications for intrauterine adhesion[J]. Chin Med J, 2017, 130(22): 2732-2737. DOI:10.4103/0366-6999.218013.
[22]ZHONG W, XIE Y, ABDALLAH M, et al. Cellular stress causes reversible, PRKAA1/2-, and proteasome-dependent ID2 protein loss in trophoblast stem cells[J]. Reproduction, 2010, 140(6): 921-930. DOI:10.1530/REP-10-0268.
[23]CABANA-DOMNGUEZ J, RONCERO C, PINEDA-CIRERA L, et al. Association of the PLCB1 gene with drug dependence[J]. Sci Rep, 2017, 7(1): 10110. DOI:10.1038/s41598-017-10207-2.
[24]BONHAM L W, EVANS D S, LIU Y M, et al. Neurotransmitter pathway genes in cognitive decline during aging: evidence for GNG4 and KCNQ2 genes[J]. Am J Alzheimers Dis Other Demen, 2018, 33(3): 153-165. DOI:10.1177/1533317517739384.
[25]KELEMEN L E, SELLERS T A, KEENEY G L, et al. Multivitamin and alcohol intake and folate receptor alpha expression in ovarian cancer[J]. Cancer Epidemiol Biomarkers Prev, 2005, 14(9): 2168-2172. DOI:10.1158/1055-9965.EPI-05-0260.
[26]PILLAI M R, CHACKO P, KESARI L A, et al. Expression of folate receptors and heterogeneous nuclear ribonucleoprotein E1 in women with human papillomavirus mediated transformation of cervical tissue to cancer[J]. J Clin Pathol, 2003, 56(8): 569-574.
[27]CLEMENTI C, TRIPURANI S K, LARGE M J, et al. Activin-like kinase 2 functions in peri-implantation uterine signaling in mice and humans[J]. PLoS Genet, 2013, 9(11): e1003863. DOI:10.1371/journal.pgen.1003863.
[28]BHAGWAT S R, CHANDRASHEKAR D S, KAKAR R, et al. Endometrial receptivity: a revisit to functional genomics studies on human endometrium and creation of HGEx-ERdb[J]. PLoS ONE, 2013, 8(3): e58419. DOI:10.1371/journal.pone.0058419.
[29]KAYA OKUR H S, DAS A, TAYLOR R N, et al. Roles of estrogen receptor-α and the coactivator MED1 during human endometrial decidualization[J]. Mol Endocrinol, 2016, 30(3): 302-313. DOI:10.1210/me.2015-1274.


 ZHAO Bang-xia,TAN Dong-mei,HE Ming-zhong,et al.Spatiotemporal expression of tumor metastasis suppressor gene CD63/ME491 in mouse endometrium[J].J Third Mil Med Univ,2007,29(13):885.
 CHEN Xiao-ling,YANG Rong,JIA Yong-cun,et al.PTEN gene expression in mouse endometria increases during embryo implantation[J].J Third Mil Med Univ,2007,29(13):2064.
 Long Xingtao,Tang Liangdan,Zhou Min,et al.Expressions of Cyclin A and P21 in ectopic and eutopic endometrial tissues of endometrtosis patients[J].J Third Mil Med Univ,2010,32(13):1038.
 CHEN Shi,LIANG Zhi-qing,YAN Jun-ling.Effect of CO2 pneumoperitoneum on expressions of β1-integrin and E-cadherins in endometrial cancer cells transplanted into nude mouse[J].J Third Mil Med Univ,2008,30(13):1283.
[6]王琳,史常旭,常青,等.子宫内膜异位症并发不孕患者子宫内膜超微结构观察[J].第三军医大学学报,2002,24(11):0.[doi:10.16016/j.1000-5404.2002.11.048 ]
 WANG Lin,SHI Chang xu,CHANG Qing,et al.[J].J Third Mil Med Univ,2002,24(13):0.[doi:10.16016/j.1000-5404.2002.11.048 ]
[7]高广正,王勇.一种解决切片染色“发白”的方法[J].第三军医大学学报,1991,13(02):0.[doi:10.16016/j.1000-5404.1991.02.022 ]
[8]何世荣,韩英,陈聪连,等.复方孕素Ⅰ号长效避孕片的避孕效果及其对子宫内膜超微结构的影响[J].第三军医大学学报,1982,04(01):0.[doi:10.16016/j.1000-5404.1982.01.007 ]
[9]朱梅刚,杨进勋,高广正,等.子宫内膜高分化腺癌的病理诊断——附10例临床病理观察[J].第三军医大学学报,1982,04(01):0.[doi:10.16016/j.1000-5404.1982.01.013 ]

更新日期/Last Update: 2019-07-08