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去泛素化酶UCHL1介导非小细胞肺癌培美曲塞耐药的机制研究.docx

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去泛素化酶UCHL1介导非小细胞肺癌培美曲塞耐药的机制研究 Title:MechanismsofUCHL1MediatedPaclitaxelResistanceinNon-SmallCellLungCancer Abstract: Non-smallcelllungcancer(NSCLC)isoneoftheleadingcausesofcancer-relateddeathsworldwide.Resistancetochemotherapy,suchaspaclitaxel,isamajorobstacleinthemanagementofNSCLC.Ubiquitincarboxyl-terminalhydrolase1(UCHL1)hasbeenimplicatedinvariouscellularprocesses,includingtumorigenesisanddrugresistance.ThispaperaimstoexplorethemechanisticroleofUCHL1inmediatingpaclitaxelresistanceinNSCLC. Introduction: Paclitaxel,amicrotubule-stabilizingagent,iscommonlyusedasafirst-linechemotherapeuticagentforNSCLC.However,thedevelopmentofpaclitaxelresistanceisacommonphenomenon,leadingtotreatmentfailureanddiseaseprogression.Understandingtheunderlyingmechanismsofpaclitaxelresistanceisvitalfordevelopingsuccessfultreatmentstrategies.UCHL1,adeubiquitinatingenzyme,hasbeenshowntoplayasignificantroleincancerpathogenesisanddrugresistance. UCHL1andTumorigenesis: UCHL1isoftenupregulatedinvariouscancers,includingNSCLC,andhasbeenassociatedwithtumorgrowth,invasion,andmetastasis.UCHL1functionsbydeubiquitinatingproteinsandregulatingtheirstabilityandactivity.Itsoverexpressionhasbeenlinkedtoincreasedcellularproliferation,inhibitionofapoptosis,andpromotionofepithelial-mesenchymaltransition(EMT).Thesecellularchangescontributetotumorprogressionanddrugresistance. InteractionwithPaclitaxel: SeveralstudieshavesuggestedapotentialassociationbetweenUCHL1expressionandpaclitaxelresistance.UCHL1hasbeenshowntomodulatetheactivityandstabilityofCriticalPaclitaxelEffluxPumps(CPEPs),suchasP-glycoprotein(P-gp)andbreastcancerresistanceprotein(BCRP).Theseeffluxpumpsactivelytransportpaclitaxeloutofcancercells,reducingitsintracellularconcentrationandeffectiveness.UCHL1couldregulatetheexpressionoractivityofCPEPs,therebypromotingdrugresistance. InvolvementinCellularSignalingPathways: UCHL1hasbeenshowntointeractwithvariouscellularsignalingpathwaysthatinfluencetheresponsetopaclitaxeltreatment.OnesuchpathwayistheAkt/mTORpat