Silencing of MicroRNA-21 Confers Radio-Sensitivity through Inhibition of the PI3KAKT Pathway and Enhancing Autophagy in Malignant Glioma Cell Lines 英文参考文献.docVIP

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Silencing of MicroRNA-21 Confers Radio-Sensitivity through Inhibition of the PI3KAKT Pathway and Enhancing Autophagy in Malignant Glioma Cell Lines 英文参考文献.doc

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Silencing of MicroRNA-21 Confers Radio-Sensitivity through Inhibition of the PI3KAKT Pathway and Enhancing Autophagy in Malignant Glioma Cell Lines 英文参考文献

SilencingofMicroRNA-21ConfersRadio-Sensitivity throughInhibitionofthePI3K/AKTPathwayand EnhancingAutophagyinMalignantGliomaCellLines Ho-ShinGwak1.,TaeHoonKim1.,GukHeuiJo1,Youn-JaeKim1,Hee-JinKwak1,JongHeonKim2, JinlongYin1,HeonYoo1,SeungHoonLee1,JongBaePark1* 1SpecificOrgansCancerBranch,ResearchInstituteandHospital,NationalCancerCenter,Goyang,Korea,2CancerCellandMolecularBiologyBranch,ResearchInstitute andHospital,NationalCancerCenter,Goyang,Korea Abstract Radiation is a core part of therapy for malignant glioma and is often provided following debulking surgery. However, resistancetoradiationoccursinmostpatients,andtheunderlyingmolecularmechanismsofradio-resistancearenotfully understood.Here,wedemonstratedthatmicroRNA21(miR-21),awell-knownonco-microRNAinmalignantglioma,isone ofthemajorplayersinradio-resistance.Radio-resistanceindifferentmalignantgliomacelllinesmeasuredbycytotoxiccell survival assay was closely associated with miR-21 expression level. Blocking miR-21 with anti-miR-21 resulted in radio- sensitizationofU373andU87cells,whereasoverexpressionofmiR-21leadtoadecreaseinradio-sensitivityofLN18and LN428cells.Anti-miR-21sustainedc-H2AXDNAfociformation,whichisanindicatorofdouble-strandDNAdamage,upto 24hoursandsuppressedphospho-Akt(ser473)expressionafterexposuretoc-irradiation.Inacellcycleanalysis,asignificant increaseintheG2/Mphasetransitionbyanti-miR-21wasobservedat48hoursafterirradiation.Interestingly,ourresults showedthatanti-miR-21increasedfactorsassociatedwithautophagosomeformationandautophagyactivity,whichwas measuredbyacidvesicularorganelles,LC3proteinexpression,andthepercentageofGFP-LC3positivecells.Furthermore, augmentedautophagybyanti-miR-21resultedinanincreaseintheapoptoticpopulationafterirradiation.Ourresultsshow that miR-21 is a pivotal molecule for circumventing radiation-induced cell death in malignant glioma cells through the regulationofautophagyandprovideanovelphenomenonfortheacquisitionofradio-resistance. Citation:GwakH-S,KimTH,JoGH,KimY-J,Kwa