ARTICLEExcessivemiR-25-3pmaturationviaN6-methyladenosinestimulatedbycigarettesmokepromotespancreaticcancerprogressionJialiangZhang1,8,RuihongBai1,8,MeiLi2,8,HuilinYe3,ChenWu4,5,ChengfengWang6,ShengpingLi1,LipingTan1,DongmeiMai1,GuolinLi3,LingPan1,YanfenZheng1,JiachunSu1,YingYe1,ZhiqiangFu3,7,ShangyouZheng3,7,ZhixiangZuo1,ZexianLiu1,QiZhao1,XuChe6,DanXie1,WeihuaJia1,Mu-ShengZeng1,WenTan4,5,RufuChen3,Rui-HuaXu1,JianZheng1&DongxinLin1,4,5N6-methyladenosine(m6A)modificationisanimportantmechanisminmiRNAprocessingandmaturation,buttheroleofitsaberrantregulationinhumandiseasesremainedunclear.Here,wedemonstratethatoncogenicprimarymicroRNA-25(miR-25)inpancreaticductepithelialcellscanbeexcessivelymaturatedbycigarettesmokecondensate(CSC)viaenhancedm6AmodificationthatismediatedbyNF-κBassociatedprotein(NKAP).Thismodificationiscatalyzedbyoverexpressedmethyltransferase-like3(METTL3)duetohypomethylationoftheMETTL3promoteralsocausedbyCSC.MaturemiR-25,miR-25-3p,suppressesPHdomainleucine-richrepeatproteinphosphatase2(PHLPP2),resultingintheactivationofoncogenicAKT-p70S6Ksignaling,whichprovokesmalignantphenotypesofpancreaticcancercells.HighlevelsofmiR-25-3paredetectedinsmokersandinpancreaticcancerstissuesthatarecorrelatedwithpoorprognosisofpancreaticcancerpatients.Theseresultscollectivelyindicatethatcigarettesmoke-inducedmiR-25-3pexcessivematurationviam6Amodificationpromotesthedevelopmentandprogressionofpancreaticcancer.https://doi.org/10.1038/s41467-019-09712-xOPEN1SunYat-senUniversityCancerCenter,StateKeyLaboratoryofOncologyinSouthChinaandCollaborativeInnovationCenterforCancerMedicine,Guangzhou,China.2DepartmentofPathology,SunYat-senUniversityCancerCenter,Guangzhou,China.3DepartmentofPancreaticobiliarySurgery,SunYat-senMemorialHospital,SunYat-senUniversity,Guangzhou,China.4DepartmentofEtiologyandCarcinogenesis,NationalCancerCenter/NationalClinicalResearchCenter/CancerHospital,ChineseAcademyofMedicalSciencesandPekingUnionMedicalCollege,Beijing,China.5CAMSKeyLaboratoryofGeneticsandGe...
