CircularRNAcircMTO1ActsastheSpongeofMicroRNA-9toSuppressHepatocellularCarcinomaProgressionDanHan,1,2*JiangxueLi,1*HuaminWang,3XiaopingSu,2JinHou,2YanGu,2ChengQian,2YunLin,2XiangLiu,2MingyanHuang,2NanLi,2WeipingZhou,4YizhiYu,2andXuetaoCao1–3NoncodingRNAsplayimportantrolesincancerbiology,providingpotentialtargetsforcancerintervention.AsanewclassofendogenousnoncodingRNAs,circularRNAs(circRNAs)havebeenrecentlyidentifiedincelldevelopmentandfunction,andcertaintypesofpathologicalresponses,generallyactingasamicroRNA(miRNA)spongetoregulategeneexpression.IdentifyingthederegulatedcircRNAsandtheirrolesincancerhasattractedmuchattention.However,theexpressionprofileandfunctionofcircRNAsinhumanhepatocellularcarcinoma(HCC)remaintobeinvestigated.Here,weanalyzedtheexpressionprofileofhumancircRNAsinHCCtissuesandidentifiedcircMTO1(mitochondrialtransla-tionoptimization1homologue;hsa_circRNA_0007874/hsa_circRNA_104135)asonecircRNAsignificantlydown-regulatedinHCCtissues.HCCpatientswithlowcircMTO1expressionhadshortenedsurvival.Byusingabiotin-labeledcircMTO1probetoperformRNAinvivoprecipitationinHCCcells,weidentifiedmiR-9asthecircMTO1-associatedmiRNA.Furthermore,silencingofcircMTO1inHCCcoulddown-regulatep21,thetargetofoncogenicmiR-9,resultinginthepromotionofHCCcellproliferationandinvasion.Inaddition,thetumor-promotingeffectofcircMTO1silencingwasblockedbymiR9inhibitor.Intratumoraladministrationofcholesterol-conjugatedcircMTO1smallinterferingRNApromotedtumorgrowthinHCC-bearingmiceinvivo.Conclusion:circMTO1suppressesHCCprogressionbyactingasthespongeofoncogenicmiR-9topromotep21expression,suggestingthatcircMTO1isapotentialtargetinHCCtreat-ment.ThedecreaseofcircMTO1inHCCtissuesmayserveasaprognosispredictorforpoorsurvivalofpatients.(HEPA-TOLOGY2017;66:1151-1164).CircularRNAs(circRNAs)representanewclassofendogenousnoncodingRNAsthatmayreg-ulategeneexpressioninmammals.UnlikelinearRNAsterminatedwith50capsand30tails,circRNAsarecharacterizedbycovalentlyclosedloopstructureswithneither50to30polaritynorp...
