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Received:5November2016 Revised:23February2017 Accepted:27February2017DOI:10.1111/ajco.12688ORIGINAL ARTICLEGenome-wideexpressionprofilingandbioinformaticsanalysisofderegulatedgenesinhumangastriccancertissueaftergastroscopyYudiMao1,2QihongZhao3ShiYin2XipingDing1,2HuaWang41DepartmentofGastroenterology,AffiliatedProvincialHospitalofAnhuiMedicalUniversity,Hefei,China2DepartmentofGeriatrics,AffiliatedProvincialHospitalofAnhuiMedicalUniversity,Hefei,China3DepartmentofFoodandNutritionHygiene,SchoolofPublicHealth,AnhuiMedicalUniver-sity,Hefei,China4DepartmentofOncology,theFirstAffiliatedHospitalofAnhuiMedicalUniversity,Hefei,ChinaCorrespondenceXipingDing,DepartmentofGeriatrics,AffiliatedProvincialHospitalofAnhuiMedicalUniversity,17LujiangRoad,Hefei,Anhui230001,China.Email:HuaWang,DepartmentofOncology,theFirstAffiliatedHospitalofAnhuiMedicalUniversity,218JixiRoad,Hefei,Anhui230032,China.Email:AbstractAim: The aim of this study was to analyze the gene expression profile and biological processesenrichedingastriccancer.Methods: We collected five human advanced gastric cancer tissues by gastroscopy and five peri-tumornormaltissuesascontrolsandexaminedthegeneexpressionchangesbymicroarray.KEGGOrthologyBasedAnnotationSystemannotationwasusedtoidentifypathwaysandbiologicalpro-cesses regulated by the deregulated genes. Proteinprotein interaction network analysis identi-fiedproteincomplexandfunctionalmodules.Wealsoselected14genesforfurtherverificationbyreal-timequantitativePolymeraseChainReaction(PCR).Results: Human gene expression profile analysis showed that 2028 deregulated genes weredetected in gastric cancer compared with the control group (at least a 2.0-fold change and P 2andaP-value0.05forthecomparisonoftumorversus peritumor in corresponding terms. The right column shows the gene names. Red-colored pixels correspond to an increased abundance ofthe mRNA in the indicated sample, whereas green pixels indicate decreased mRNA levels. (A) Genes involved in cell migration. (B) DeregulatedgenesinNF-Bpathways.(C)Angiogenesisgenechangesingastriccancertissues.(D)H.pyloriinfectionderegulatedgenesalsoinvolvedingastriccancer.(E)Deregulatedgenesintheinflammationresponseingastriccancer.(F)DeregulatedgenesintheJAK-STATpathwaysCreportofassociationwithgastriccancer.WefoundthattheexpressionofCXCL17wasdownregulatedingastriccancer.Asanovelchemokineingastriccancer,CXCL17mightprovideanewmoleculartargetforthepathogenesisofgastriccancer.In addition, KOBAS annotation enriched many genes that arerelated to cell proliferation and apoptosis. The up-regulated genes,BCL6, TLR2, FBP1 and MT1G, have been reported in gastric cancer,but the downregulated genes, including MT1F and MT1B, were rarelyreported. The genes playing negative roles in cell migration, ABHD6and TIE1, and the genes with a positive role, HAS2 and GCNT2,havescarcely been mentioned in relation to gastric cancer. Interestingly,bioinformatics analysis showed that H. pylori infection status, alco-hol dependence, and lipid metabolism were enriched, suggesting thatthese factors might influence epigenetic changes and may have a cer-tainrelationshipwiththeoccurrenceofgastriccancer.An important result of this study is the identification of a seriesof genes that are deregulated in gastric cancer compared with adja-cent noncancerous tissues. In addition, our study has yielded essen-tial information regarding which genes may be involved in gastric can-cer pathogenesis. We performed integrative analysis of mRNAs andgene expression data, and the transcription level of 14 abnormallyexpressed genes were verified by RT-qPCR. In addition, we collectedmore matched samples to verify our results, and they were consis-tent with the results of the microarray (data not shown). OTX1 hasbeen described as a critical molecule for neocortex organization anddetermines progenitor behavior and histogenesis in mammals.25InMAO ET AL. 7addition, it has been reported that the P53 protein directly inducesOTX1 expressionbyactingonitspromoterinbreastcancer,andsyner-gisticallyeffectedcancerstemcelldifferentiation.26Ourdatashowedthe OTX1 mRNAwasupregulatedingastriccancer,whichhasnotpre-viously been reported. Further studies are needed to explore the spe-cific function of OXT1 in gastric cancer. CEBPB was also found to beupregulated in gastric cancer, and it acts as a prognostic marker ofgastric cancer, promoting tumor proliferation.27,28CCDC125 acts asa regulator of cell motility through RHOA, RAC1 and CDC42,29andwas downregulated in gastric cancer. This newly identified gastriccancer related gene may have many potential features waiting to bediscovered.Towards the identification of protein complex and functional mod-ules, we integrated PPI network and genes expression data. But thisstudy does not provide more information on the possible roles ofmostofthemRNAsidentifiedingastriccancer.AlthoughsomemRNAsmight participate in the pathogenesis of gastric cancer, others mayonly be associated with clinical features and diagnosis and prognos-tic biomarkers. This analysis will be the focus of our future work and alarger sample size is needed for further validation and research. How-ever,ourexperimentscanbeusedforreferenceinfuturestudiestheo-reticallyandclinically.In conclusion, we identified 2028 abnormally expressed genes inhumangastriccancertissues.Analysisofpathways,GOterms,anddis-easesthathelpustounderstandthemolecularmechanismsregulatingthe pathogenesis of gastric cancer are of utmost importance for thedevelopment of new therapies for gastric cancer. Our results providea global perspective to increase our understanding of gastric cancer,the development of new therapeutic strategies and the identificationofbiomarkers.ACKNOWLEDGMENTSThis work was supported by the National Natural Science Founda-tionofChina(81470879/H0318toS.Yin),NewCenturyExcellentTal-entsinUniversity,MinistryofEducationofChina(No.NCET-13-0644to H. Wang), Public welfare Technology Application Research linkageProject of Anhui Province of China (No. 1604f0804018 to X. P. Ding)andWanjiangScholarsProgramofAnhuiProvinceofChinatoH.Wang.Noconflictsofinterestexistforanyoftheauthors.REFERENCES1. 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Recursive partition analysis ofperitoneal and systemic recurrence in patients with gastric cancerwhounderwentD2gastrectomy:Implicationsforneoadjuvanttherapyconsideration.JSurgOncol.2016;114:859864.9. Zhou F, Cheng L, Qiu LX, et al. Associations of potentially functionalvariants in IL-6, JAKs and STAT3 with gastric cancer risk in an easternChinesepopulation.Oncotarget.2016;7:2811228123.10. NeculaLG,Chivu-EconomescuM,StanciulescuEL,etal.IL-6andIL-11as markers for tumor aggressiveness and prognosis in gastric adeno-carcinoma patients without mutations in Gp130 subunits. JGastroin-testinLiverDis.2012;21:2329.11. Yang Z, Guo L, Liu D, et al. Acquisition of resistance to trastuzumab ingastriccancercellsisassociatedwithactivationofIL-6/STAT3/Jagged-1/Notch positive feedback loop. Oncotarget. 2015;6:50725087.12. Zhang JL, Liu XZ, Wang PY, et al. Targeting HCCR expressionresensitizes gastric cancer cells to chemotherapy via down-regulating the activation of STAT3. 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AsanoN,ImataniA,WatanabeT,etal.Cdx2Expressionandintestinalmetaplasiainducedbyh.pyloriinfectionofgastriccellsisregulatedbynod1-mediatedinnateimmuneresponses.CancerRes.2016;76:11351145.18. Kwon CH, Moon HJ, Park HJ, et al. S100A8 and S100A9 promotesinvasionandmigrationthroughp38mitogen-activatedproteinkinase-dependent NF-kappaB activation in gastric cancer cells. Mol Cell.2013;35:226234.19. Dey S, Stalin S, Gupta A, et al. Matrix metalloproteinase3 gene pro-moterpolymorphismsandtheirhaplotypesareassociatedwithgastriccancer risk in eastern Indian population. Mol Carcinog. 2012;51(Suppl1):E42E53.20. VerbekeH,GeboesK,VanDammeJ,etal.TheroleofCXCchemokinesinthetransitionofchronicinflammationtoesophagealandgastriccan-cer.BiochimBiophysActa.2012;1825:117129.21. Yanagie H, Hisa T, Ono M, et al. Chemokine and chemokine receptorrelated to cancer metastasis. Gan to Kagaku Ryoho Cancer Chemother.2010;37:20522057.22. He S, Wang L, Wu Y, et al. CCL3 and CCL20-recruited dendriticcells modified by melanoma antigen gene-1 induce anti-tumor immu-8 MAO ET AL.nity against gastric cancer ex vivo and in vivo. J Exp Clin Cancer Res.2010;29:37./10.1186/1756-9966-29-37.23. Li L, Yan J, Xu J, et al. CXCL17 expression predicts poor prognosisand correlates with adverse immune infiltration in hepatocellular car-cinoma.PloSOne.2014;9:e110064.24. Ohlsson L, Hammarstrom ML, Lindmark G, et al. Ectopic expres-sion of the chemokine CXCL17 in colon cancer cells. Br J Cancer.2016;114

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