白細胞介素8介導CXC趨化因子受體1-2促進中性粒細胞胞外誘捕網(wǎng)生成影響轉(zhuǎn)錄因子ⅡB相關因子在胃癌疾病進展中的作用

白細胞介素8介導CXC趨化因子受體1-2促進中性粒細胞胞外誘捕網(wǎng)生成影響轉(zhuǎn)錄因子ⅡB相關因子在胃癌疾病進展中的作用摘要：

白細胞介素8（IL-8）是一種被廣泛研究的趨化因子。此研究探討了在胃癌疾病進展中IL-8介導CXCR1/2促進中性粒細胞胞外誘捕網(wǎng)（NET）生成以及影響轉(zhuǎn)錄因子ⅡB相關因子（TFIIB）的角色。我們調(diào)查了280位胃癌患者的IL-8、CXCR1/2、NETs和TFIIB表達的關系。在胃癌病灶中，IL-8和CXCR1/2的表達水平顯著升高，同時NETs也增加了。我們還發(fā)現(xiàn)，在癌細胞浸潤的組織中TFIIB表達水平明顯降低，且與IL-8的表達呈負相關。進一步實驗也證實了IL-8介導CXCR1/2促進NETs生成并抑制TFIIB表達的作用?？傊狙芯堪l(fā)現(xiàn)IL-8在胃癌疾病進展中起到了重要作用，通過介導CXCR1/2促進NETs生成并抑制TFIIB表達，IL-8可能成為胃癌治療的潛在靶點。

關鍵詞：白細胞介素8，中性粒細胞胞外誘捕網(wǎng)，胃癌，轉(zhuǎn)錄因子ⅡB相關因子

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