Evidence for the Complexity of MicroRNA-Mediated Regulation in Ovarian Cancer A Systems Approach 英文参考文献.docVIP

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Evidence for the Complexity of MicroRNA-Mediated Regulation in Ovarian Cancer A Systems Approach 英文参考文献.doc

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Evidence for the Complexity of MicroRNA-Mediated Regulation in Ovarian Cancer A Systems Approach 英文参考文献

EvidencefortheComplexityofMicroRNA-Mediated RegulationinOvarianCancer:ASystemsApproach ShubinW.Shahab1,2,LilyaV.Matyunina1,2,3,RomanMezencev1,2,3,L.DeEtteWalker1,2,3,NathanJ. Bowen3,4,BenedictB.Benigno3,JohnF.McDonald1,2,3* 1SchoolofBiology,GeorgiaInstituteofTechnology,Atlanta,Georgia,UnitedStatesofAmerica, 2ParkerH.PetitInstituteforBioengineeringandBioscience,Georgia Institute ofTechnology,Atlanta,Georgia, United States ofAmerica, 3Ovarian CancerInstitute,Atlanta,Georgia, United States ofAmerica, 4Department ofBiological Sciences,ClarkAtlantaUniversity,Atlanta,Georgia,UnitedStatesofAmerica Abstract MicroRNAs(miRNAs)areshort(,22nucleotides)regulatoryRNAsthatcanmodulategeneexpressionandareaberrantly expressedinmanydiseasesincludingcancer.PreviousstudieshaveshownthatmiRNAsinhibitthetranslationandfacilitate thedegradationoftheirtargetedmessengerRNAs(mRNAs)makingthemattractivecandidatesforuseincancertherapy. However, the potential clinical utility of miRNAs in cancer therapy rests heavily upon our ability to understand and accurately predict the consequences of fluctuations in levels of miRNAs within the context of complex tumor cells. To evaluate the predictive power of current models, levels of miRNAs and their targeted mRNAs were measured in laser capturedmicro-dissected(LCM)ovariancancerepithelialcells(CEPI)andcomparedwithlevelspresentinovariansurface epithelialcells(OSE).WefoundthatthepredictedinversecorrelationbetweenchangesinlevelsofmiRNAsandlevelsof their mRNA targets held for only ,11% of predicted target mRNAs. We demonstrate that this low inverse correlation betweenchangesinlevelsofmiRNAsandtheirtargetmRNAsinvivoisnotmerelyanartifactofinaccuratemiRNAtarget predictionsbutthelikelyconsequenceofindirectcellularprocessesthatmodulatetheregulatoryeffectsofmiRNAsinvivo. Our findings underscore the complexities of miRNA-mediated regulation in vivo and the necessity of understanding the basisofthesecomplexitiesincancercellsbeforethetherapeuticpotentialofmiR