Apoptosis Induced by Knockdown of uPAR and MMP-9 is Mediated by Inactivation of EGFRSTAT3 Signaling in Medulloblastoma 英文参考文献.docVIP

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Apoptosis Induced by Knockdown of uPAR and MMP-9 is Mediated by Inactivation of EGFRSTAT3 Signaling in Medulloblastoma 英文参考文献.doc

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Apoptosis Induced by Knockdown of uPAR and MMP-9 is Mediated by Inactivation of EGFRSTAT3 Signaling in Medulloblastoma 英文参考文献

ApoptosisInducedbyKnockdownofuPARandMMP-9is MediatedbyInactivationofEGFR/STAT3Signalingin Medulloblastoma RamaprasadaRaoKotipatruni1.,ArunKumarNalla1.,SwapnaAsuthkar1,ChristopherS.Gondi1, DzungH.Dinh2,JastiS.Rao1,2* 1Department of Cancer Biology and Pharmacology, University of Illinois College of Medicine at Peoria, Peoria, Illinois, United States of America, 2Department of Neurosurgery,UniversityofIllinoisCollegeofMedicineatPeoria,Peoria,Illinois,UnitedStatesofAmerica Abstract Background:Medulloblastomaisahighlyinvasivecancerofcentralnervoussystemdiagnosedmainlyinchildren.Matrix metalloproteinase-9(MMP-9)andurokinaseplasminogenactivatorreceptor(uPAR)areoverexpressedinseveralcancers andwellestablished fortheirroles intumorprogression. Thepresentstudy isaimed todeterminetheconsequences of targetingthesemoleculesonmedulloblastomaprogression. Methodology/PrincipalFindings:Radiationisoneoftheforemostmethodsappliedfortreatingcancerandconsiderable evidenceshowedthatradiationelevateduPARandMMP-9expressioninmedulloblastomacell.Thereforeeffortsaremade totargetthesemoleculesinnon-irradiatedandirradiatedmedulloblastomacells.OurresultsshowedthatsiRNA-mediated knockdown of uPAR and MMP-9, either alone or in combination with radiation modulated a series of events leading to apoptosis. Down regulation of uPAR and MMP-9 inhibited the expression of anti-apoptotic molecules like Bcl-2, Bcl-xL, survivin,XIAPandcIAPI;activatedBIDcleavage,enhancedtheexpressionofBakandtranslocatedcyctochromeCtocytosol. Capsase-3 and -9 activities were also increased in uPAR- and MMP-9-downregulated cells. The apoptosis induced by targeting MMP-9 and uPAR was initiated by inhibiting epidermal growth factor receptor (EGFR) mediated activation of STAT3andNF-kBrelatedsignalingmolecules.SilencinguPARandMMP-9inhibitedDNAbindingactivityofSTAT3andalso reduced the recruitment of STAT3 protein at the promoter region of Bcl-2 and survivin genes. Our results suggest that inhibitinguPARandMMP-9reducedtheexpres