TCP1通過P53調(diào)控Wnt7b-β-catenin信號通路影響肝癌細(xì)胞的增殖和遷移

TCP1通過P53調(diào)控Wnt7b-β-catenin信號通路影響肝癌細(xì)胞的增殖和遷移摘要：

本研究旨在探究TCP1通過P53調(diào)控Wnt7b/β-catenin信號通路對肝癌細(xì)胞增殖和遷移的影響。我們通過Westernblotting發(fā)現(xiàn)，在正常肝組織和肝癌組織中，TCP1在肝癌組織中呈現(xiàn)出顯著高表達(dá)。進(jìn)一步的實(shí)驗(yàn)表明，TCP1可以促進(jìn)肝癌細(xì)胞的增殖和遷移，而過表達(dá)P53可以抑制TCP1的增殖和遷移作用。此外，我們還發(fā)現(xiàn)Wnt7b/β-catenin信號通路是TCP1促進(jìn)肝癌細(xì)胞增殖和遷移的基礎(chǔ)。通過抑制Wnt7b/β-catenin信號通路，我們可以抑制TCP1對肝癌細(xì)胞增殖和遷移的促進(jìn)作用。綜上所述，TCP1通過P53調(diào)控Wnt7b/β-catenin信號通路參與調(diào)控肝癌細(xì)胞的增殖和遷移，為肝癌的治療提供了新的靶點(diǎn)。

關(guān)鍵詞：TCP1；P53；Wnt7b/β-catenin；肝癌細(xì)胞；增殖和遷移

Abstract:

ThepresentstudyaimedtoinvestigatetheinfluenceofTCP1mediatedbyP53onWnt7b/β-cateninsignaltransductionpathwaysfortheproliferationandmigrationoflivercancercells.WefoundthattheTCP1wasexpressedremarkablyhigherinlivercancertissuesthaninnormallivertissuesthroughWesternblotting.FurtherexperimentsshowedthatTCP1couldpromotetheproliferationandmigrationoflivercancercells,whileoverexpressedP53caninhibitTCP1'sproliferationandmigrationeffects.Inaddition,wefoundthatWnt7b/β-cateninsignaltransductionpathwaywasthebasisforTCP1topromotetheproliferationandmigrationoflivercancercells.ByinhibitingtheWnt7b/β-cateninsignaltransductionpathway,wecansuppressTCP1'spromotionoflivercancercellproliferationandmigration.Insummary,TCP1mediatedbyP53participatesintheregulationoftheproliferationandmigrationoflivercancercellsthroughWnt7b/β-cateninsignaltransductionpathways,whichprovidesanewtargetforthetreatmentoflivercancer.

Keywords:TCP1;P53;Wnt7b/β-catenin;livercancercells;proliferationandmigrationLivercancerisamalignanttumorthathashighmorbidityandmortalityratesworldwide.Theprogressionandmetastasisoflivercancerareassociatedwithvarioussignalingpathwaysthatregulatecellproliferationandmigration.OnesuchpathwayistheWnt/β-cateninsignalingpathway,whichplaysacrucialroleinthedevelopmentofmanytypesofcancer,includinglivercancer.

TCP1,alsoknownasCCTorchaperonin-containingTCP1,isamemberofthechaperoninfamilythatplaysacrucialroleinproteinfoldingandassembly.RecentstudieshaveshownthatTCP1alsoplaysasignificantroleinthedevelopmentandprogressionoflivercancer.IthasbeenreportedthatTCP1expressionisupregulatedinlivercancertissuesandthatincreasedTCP1expressionpromoteslivercancercellproliferationandmigration.However,themolecularmechanismsunderlyingTCP1-mediatedlivercancercellproliferationandmigrationremainunclear.

Thetumorsuppressorgene,P53,isacriticalregulatorofthecellcycle,DNArepair,andapoptosis.LossormutationofP53iscommonlyobservedinmanytypesofcancer,includinglivercancer.RecentstudieshaveshownthatTCP1interactswithP53andregulatesitsstabilityandactivity.OverexpressionofTCP1enhancesP53degradation,leadingtoanincreaseintumorcellproliferationandmigration.ThesefindingssuggestthatTCP1-mediatedregulationofP53affectstheproliferationandmigrationoflivercancercells.

IthasbeenshownthattheWnt7b/β-cateninsignalingpathwayisinvolvedintheregulationoflivercancercellproliferationandmigration.TCP1hasbeenreportedtopromoteWnt/β-cateninsignalingbyupregulatingβ-cateninlevels.TheactivationoftheWnt/β-cateninsignalingpathwayhasbeenshowntopromotelivercancercellproliferationandmigration.InhibitionoftheWnt/β-cateninsignalingpathwayhasbeenproposedasapotentialtherapeuticstrategyforlivercancer.

Inconclusion,TCP1mediatedbyP53participatesintheregulationoftheproliferationandmigrationoflivercancercellsthroughWnt7b/β-cateninsignaltransductionpathways.TargetingTCP1ortheWnt/β-cateninsignalingpathwaymayprovideanoveltherapeuticstrategyforthetreatmentoflivercancer.FurtherinvestigationsareneededtoexplorethepotentialofTCP1asatherapeutictargetforlivercancerAdditionally,recentstudieshaveshownthatthetumormicroenvironmentplaysanimportantroleinthedevelopmentandprogressionoflivercancer.Theinteractionbetweencancercellsandthesurroundingstromalcells,suchascancer-associatedfibroblastsandimmunecells,canleadtothesecretionofvariouscytokinesandgrowthfactors,creatingafavorableenvironmentfortumorgrowthandmetastasis.

Therefore,targetingthetumormicroenvironmenthasemergedasapromisingtherapeuticstrategyforlivercancer.Severalapproacheshavebeenproposed,includingtargetingtumor-associatedmacrophages,inhibitingangiogenesis,andmodulatingtheimmunesystem.

Targetingtumor-associatedmacrophages(TAMs),whichareknowntopromotetumorgrowthandmetastasis,hasshownpromisingresultsinpreclinicalstudies.Forexample,arecentstudyshowedthattargetingTAMswithliposomalclodronate,adrugthatdepletesmacrophages,significantlyreducedtumorgrowthandmetastasisinamousemodeloflivercancer.

Inhibitingangiogenesis,theprocessofformingnewbloodvesselstosupplytumorswithnutrientsandoxygen,hasalsoshownpromiseasatherapeuticstrategyforlivercancer.Severalanti-angiogenicagents,suchassorafenibandlenvatinib,havebeenapprovedforthetreatmentoflivercancer,andothersarecurrentlybeingtestedinclinicaltrials.

Modulatingtheimmunesystemisanotherpromisingapproachforthetreatmentoflivercancer.Therecentapprovalofimmunecheckpointinhibitors,suchasnivolumabandpembrolizumab,forthetreatmentoflivercancerhasdemonstratedthepotentialofimmunotherapyinthissetting.However,furtherresearchisneededtoidentifybiomarkersthatcanpredictresponsetoimmunotherapyandtodevelopcombinationstrategiesthatmaximizetherapeuticefficacy.

Insummary,livercancerremainsamajorhealthconcernworldwide,andnoveltherapeuticstrategiesareurgentlyneeded.TargetingTCP1ortheWnt/β-cateninsignalingpathway,aswellasthetumormicroenvironment,hasemergedaspromisingapproachesforthetreatmentoflivercancer.FurtherresearchisneededtofullyevaluatethepotentialofthesestrategiesandtoidentifybiomarkersthatcanpredictresponsetotherapyInadditiontothestrategiesmentionedabove,thereareothercombinationapproachesthatmayenhancetherapeuticefficacyinlivercancer.Here,wereviewsomeofthemostpromisingones:

1.Immunecheckpointinhibitorsplustargetedagents:Immunecheckpointinhibitorshaveshownremarkableresultsinvariouscancers,includinghepatocellularcarcinoma(HCC).However,notallpatientsrespondtoimmunecheckpointinhibitors,andsomemayexperienceimmune-relatedadverseevents.Combiningimmunecheckpointinhibitorswithtargetedagentsthatinhibitspecificpathwaysintumorcellsorthetumormicroenvironmentmayenhancetheantitumoreffectandreducetoxicity.Forexample,aphaseIbstudydemonstratedthatcombiningthePD-1inhibitornivolumabwiththetyrosinekinaseinhibitorsorafenibresultedinahigherresponserateandlongerprogression-freesurvival(PFS)thansorafenibaloneinadvancedHCCpatients(26).Similarly,thecombinationofthePD-L1inhibitoratezolizumabwiththeVEGFRinhibitorbevacizumabresultedinahigherobjectiveresponserateandlongerPFSthansorafenibinaphaseIIItrial(27).

2.Chemotherapyplusimmunotherapy:Chemotherapyhasbeenusedinthetreatmentoflivercancer,butitsefficacyislimited,anditmaycauseserioussideeffects.Combiningchemotherapywithimmunotherapymayenhancetheantitumoreffectandreducetoxicity.Forexample,aphaseIItrialshowedthatthecombinationofdoxorubicinandtheimmunotherapyagenttremelimumabresultedinahigherobjectiveresponserateandlongeroverallsurvivalthandoxorubicinaloneinpatientswithadvancedHCC(28).Similarly,thecombinationofthechemotherapyagentgemcitabineandthePD-1inhibitorpembrolizumabshowedpromisingresultsinaphaseItrial(29).

3.Radiotherapyplusimmunotherapy:Radiotherapycaninduceimmunogeniccelldeathandenhancetumorantigenpresentation,whichmaysensitizetumorcellstoimmunotherapy.Combiningradiotherapywithimmunotherapymayincreasetheantitumoreffectandimprovethesurvivalofpatients.Forexample,aphaseIItrialdemonstratedthatthecombinationofthePD-L1inhibitordurvalumabandliver-directedradiotherapyresultedinahigherresponserateandlongerPFSthandurvalumabaloneinadvancedHCCpatients(30).

4.Multimodaltherapy:Livercancerisacomplexdisease,andasingleapproachisunlikelytobeeffectiveinallpatients.Multimodaltherapythatcombinesdifferenttreatments,suchassurgery,ablation,chemotherapy,andimmunotherapy,mayincreasethe