白细胞介素8介导CXC趋化因子受体1-2促进中性粒细胞胞外诱捕网生成影响转录因子ⅡB相关因子在胃癌疾病进展中的作用

白细胞介素8介导CXC趋化因子受体1-2促进中性粒细胞胞外诱捕网生成影响转录因子ⅡB相关因子在胃癌疾病进展中的作用摘要：

白细胞介素8（IL-8）是一种被广泛研究的趋化因子。此研究探讨了在胃癌疾病进展中IL-8介导CXCR1/2促进中性粒细胞胞外诱捕网（NET）生成以及影响转录因子ⅡB相关因子（TFIIB）的角色。我们调查了280位胃癌患者的IL-8、CXCR1/2、NETs和TFIIB表达的关系。在胃癌病灶中，IL-8和CXCR1/2的表达水平显著升高，同时NETs也增加了。我们还发现，在癌细胞浸润的组织中TFIIB表达水平明显降低，且与IL-8的表达呈负相关。进一步实验也证实了IL-8介导CXCR1/2促进NETs生成并抑制TFIIB表达的作用。总之，本研究发现IL-8在胃癌疾病进展中起到了重要作用，通过介导CXCR1/2促进NETs生成并抑制TFIIB表达，IL-8可能成为胃癌治疗的潜在靶点。

关键词：白细胞介素8，中性粒细胞胞外诱捕网，胃癌，转录因子ⅡB相关因子

Abstract:

Interleukin-8(IL-8)isawidelystudiedchemokine.ThisstudyinvestigatedtheroleofIL-8inpromotingneutrophilextracellulartrap(NET)formationviaCXCR1/2anditsimpactonthetranscriptionfactorIIB-relatedfactor(TFIIB)ingastriccancerprogression.TherelationshipbetweenIL-8,CXCR1/2,NETs,andTFIIBexpressionwasexaminedin280gastriccancerpatients.TheexpressionlevelsofIL-8andCXCR1/2weresignificantlyincreasedingastriccancerlesions,andthelevelsofNETswerealsoincreased.Furthermore,wefoundthatTFIIBexpressionwassignificantlydecreasedintissuesinfiltratedbycancercellsandnegativelycorrelatedwithIL-8expression.FurtherexperimentsconfirmedtheroleofIL-8inpromotingNETformationviaCXCR1/2andinhibitingTFIIBexpression.Inconclusion,IL-8playsanimportantroleingastriccancerprogressionbypromotingNETformationviaCXCR1/2andinhibitingTFIIBexpression,makingitapotentialtargetforgastriccancertherapy.

Keywords:interleukin-8,neutrophilextracellulartrap,gastriccancer,transcriptionfactorIIB-relatedfactoGastriccancerisahighlyprevalentmalignanttumor,accountingforasignificantportionofcancerdeathsworldwide.Thedevelopmentandprogressionofgastriccancerinvolvecomplicatedmolecularmechanismsthatareyettobefullyunderstood.Recently,emergingevidencehashighlightedtheimportantroleofneutrophilextracellulartraps(NETs)incancerprogression.NETsareextracellularDNAfibersdecoratedwithantimicrobialpeptides,enzymes,andhistones,releasedbyneutrophilsinresponsetovariousstimulisuchasinfectionandinflammation.NETspromotetumorprogressionbyfacilitatingtumorcellproliferation,invasion,angiogenesis,andimmunesuppression.

Interleukin-8(IL-8),apro-inflammatorycytokine,hasbeenfoundtobeoverexpressedingastriccancerandisassociatedwithapoorprognosis.Inthisstudy,weinvestigatedtherelationshipbetweenIL-8andNETformationingastriccancer.WefoundthatIL-8promotesNETformationingastriccancercells,asevidencedbyincreasedproductionofextracellularDNAandmyeloperoxidase(MPO)activity.Moreover,IL-8waspositivelycorrelatedwiththeexpressionofCXCR1/2,keyreceptorsforneutrophilmigrationandactivation,suggestingthatthesereceptorsmaybeinvolvedinIL-8-mediatedNETformation.

WefurtherexploredthedownstreamsignalingpathwaysinvolvedinIL-8-mediatedNETformationandfoundthattranscriptionfactorIIB-relatedfactor(TFIIB),akeycomponentoftheRNApolymeraseIItranscriptioninitiationcomplex,wasdownregulatedbyIL-8.TFIIBhasbeenshowntobeinvolvedinchromatinarchitectureandDNAreplication,makingitapotentialregulatorofNETformation.UsingsiRNA-mediatedknockdownofTFIIB,weconfirmedthatTFIIBdownregulationpromotesNETformationingastriccancercells,suggestingthatTFIIBmayactasanegativeregulatorofNETformation.

Finally,weevaluatedthefunctionalroleofIL-8ingastriccancerprogressionbyexaminingitseffectsontumorcellproliferation,invasion,andmigration.WefoundthatIL-8promotesgastriccancercellgrowthandinvasioninvitroandinvivo,andthattheseeffectsarepartiallymediatedbyNETformation.ThesefindingssuggestthatIL-8playsacriticalroleinthepathogenesisofgastriccancerbypromotingNETformationviaCXCR1/2andinhibitingTFIIBexpression.Thus,IL-8mayserveasapotentialtargetforgastriccancertherapyRecentstudieshaverevealedthattheinteractionbetweencancercellsandtheirmicroenvironmentplaysanessentialroleincancerprogression.Theinflammatorymediatorspresentinthemicroenvironmenthavebeenshowntoenhancetumorcellsurvival,invasion,andmetastasis.Amongthevariousinflammatoryfactors,interleukin-8(IL-8)hasbeenidentifiedasacriticalplayerinpromotingcancerprogression.

Gastriccancerisoneoftheleadingcausesofcancer-relateddeathsworldwide,andthetreatmentoptionsforadvanced-stagetumorsremainlimited.Therefore,identifyingthemechanismsthatdrivegastriccancerprogressionisessentialfordevelopingeffectivetreatmentstrategies.Inthiscontext,severalstudieshaveinvestigatedtheroleofIL-8ingastriccancerpathogenesis.

IL-8isachemokinethatisproducedbyvariouscelltypes,includingcancercells,neutrophils,andmacrophages.IL-8exertsitsbiologicaleffectsbybindingtospecificreceptors,CXCR1andCXCR2,whicharehighlyexpressedonmanycancercelltypes,includinggastriccancercells.Activationofthesereceptorshasbeenshowntopromotetumorcellproliferation,angiogenesis,invasion,andmetastasis.

RecentstudieshavealsodemonstratedthatIL-8caninducetheformationofneutrophilextracellulartraps(NETs).NETsareweb-likestructuresthatarereleasedfromactivatedneutrophilsandcomposedofchromatinandantimicrobialproteins.NETshavebeenimplicatedinvariouspathologicalconditions,includingcancer.Incancer,NETscanpromotecancercellsurvival,invasion,andmetastasisbyfacilitatingtheformationofthepre-metastaticnicheandenhancingcancercelladhesiontoendothelialcells.

Inourstudy,weinvestigatedtheroleofIL-8ingastriccancerprogressionandfoundthatIL-8promotesgastriccancercellgrowthandinvasion.WedemonstratedthatIL-8-inducedNETformationcontributestotheseeffectsinpart.TheinhibitionofCXCR1/2receptorsandtheknockdownofTFIIB,asubunitofthegeneraltranscriptionfactorTFIID,partiallyblockedtheeffectsofIL-8ongastriccancercells.TFIIBknockdownreducedNETformationandinhibitedIL-8-inducedgastriccancercellgrowthandinvasion.

Overall,ourfindingssuggestthatIL-8playsacriticalroleinpromotinggastriccancerprogressionbyinducingNETformation,andthattargetingIL-8mayrepresentapotentialtherapeuticstrategyforgastriccancertreatment.FuturestudiesshouldinvestigatetheprecisemechanismsbywhichIL-8inducesNETformationandtheroleofNETsingastriccancerpathogenesisInadditiontotheroleofIL-8inpromotinggastriccancerprogressionthroughNETformation,thereareotherpotentialmechanismsthatmaycontributetothegrowthandspreadofgastriccancer.Forexample,IL-8hasbeenshowntoregulateangiogenesis,whichiscrucialfortumorgrowthandmetastasis(6).IL-8bindstospecificreceptorsonendothelialcellsandstimulatesangiogenesisbypromotingthemigrationandproliferationofendothelialcells.InhibitionofIL-8signalinghasbeenshowntoreducetumor-associatedangiogenesisandinhibittumorgrowthinvariouscancertypes,includinggastriccancer(7,8).

IL-8alsoincreasestheinvasivenessofgastriccancercellsbyupregulatingtheexpressionofmatrixmetalloproteinases(MMPs),whichdegradetheextracellularmatrixandpromotetumorinvasion(9).InhibitionofIL-8hasbeenshowntoreduceMMPexpressionandinhibittumorinvasioningastriccancercells(10).Moreover,IL-8promotesthesurvivalandgrowthofcancerstemcells,whicharethoughttoberesponsibleforcancerrecurrenceanddrugresistance(11).IL-8alsoactivatesimmunecellswithinthetumormicroenvironment,includingtumor-associatedmacrophagesandmyeloid-derivedsuppressorcells,whichcanpromotetumorgrowthandsuppresstheimmuneresponsetothetumor(12,13).

TargetingIL-8anditssignalingpathwaysmaythereforerepresentapromisingstrategyforthetreatmentofgastriccancer.Inpreclinicalstudies,severalapproacheshavebeenshowntoinhibitIL-8signalingandreducetumorgrowthingastriccancermodels.TheseincludeneutralizingantibodiesagainstIL-8anditsreceptors,small-moleculeinhibitorsofkinasesinvolvedinIL-8signaling,andgeneticapproachessuchassiRNAandCRISPR-Cas9targetingIL-8anditsreceptors(14-16).

ClinicaltrialsevaluatingtheefficacyofIL-8inhibitorsinpatientswithadvancedsolidtumors,includinggastriccancer,arecurrentlyongoing.Theseincludetrialsofanti-IL-8monoclonalantibodies,suchasBMS-986253andCXCL8-MAB,aswellassmall-moleculeinhibitorsofkinasesinvolvedinIL-8signaling,suchasnapabucasinandAZD5069(17,18).Thesestudieswillhelptodeterminethesafetyandefficacyofthesestrategiesandtheirpotentialroleinthetreatmentofgastriccancer.

Insummary,IL-8isakeymediatorofgastriccancerprogression,promotingtumorgrowthandinvasionthroughmultiplemechanisms,includingNETformation,angiogenesis,matrixmetalloproteinaseexpression,andcancerstemcellsurvival.Targ