RESEARCHOpenAccessExosome-transmittedmiR-128-3pincreasechemosensitivityofoxaliplatin-resistantcolorectalcancerTongLiu1,XinZhang2,LutaoDu1,YunshanWang1,XiaomingLiu3,HuiTian4,LiliWang2,PeilongLi1,YinghuiZhao1,WeiliDuan1,YujiaoXie1,ZhaoweiSun5andChuanxinWang1*AbstractBackground:Oxaliplatinresistanceisamajorchallengefortreatmentofadvancedcolorectalcancer(CRC).Bothacquisitionofepithelial-mesenchymaltransition(EMT)andsuppresseddrugaccumulationincancercellscontributestodevelopmentofoxaliplatinresistance.AberrantexpressionofsmallnoncodingRNA,miR-128-3p,hasbeenshowntobeakeyregulatorintumorigenesisandcancerdevelopment.However,itsrolesintheprogressionofCRCandoxaliplatin-resistancearelargelyunknown.Methods:Oxaliplatin-resistantCRCandnormalintestinalFHCcellsweretransfectedwithamiR-128-3pexpressionlentivirus.Aftertransfection,FHC-derivedexosomeswereisolatedandco-culturedwithCRCcells.miR-128-3pexpressioninresistantCRCcells,FHCcells,andexosomeswasquantifiedbyquantitativereal-timePCR(RT-qPCR).ThemRNAandproteinlevelsofmiR-128-3ptargetgenesinresistantCRCcellswerequantifiedbyRT-qPCRandwesternblot,respectively.TheeffectsofmiR-128-3ponCRCcellviability,apoptosis,EMT,motilityanddrugeffluxwereevaluatedbyCCK8,flowcytometry,Transwellandwoundhealingassays,immunofluorescence,andatomicabsorptionspectrophotometry.XenograftmodelswereusedtodeterminewhethermiR-128-3ploadedexosomescanre-sensitizeCRCcellstooxaliplatininvivo.Results:Inourestablishedstableoxaliplatin-resistantCRCcelllines,invitroandvivostudiesrevealedmiR-128-3psuppressedEMTandincreasedintracellularoxaliplatinaccumulation.Importantly,ourresultsindicatedthatlowermiR-128-3pexpressionwasassociatedwithpooroxaliplatinresponseinadvancedhumanCRCpatients.Moreover,datashowedthatmiR-128-3p-transfectedFHCcellseffectivelypackagedmiR-128-3pintosecretedexosomesandmediatedmiR-128-3pdeliverytooxaliplatin-resistantcells,improvingoxaliplatinresponseinCRCcellsbothinvitroandinvivo.Inaddition,miR-128-3poverexpressionup-regulatedE-cadherinlevelsandinhibite...
