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RNA-binding protein LIN28B inhibits apoptosis through regulation of the AKT2/FOXO3A/BIM axis in ovarian cancer cells

查看全文 作　　者：Xiaojuan [1,2]Lin;Jianfeng [1]Shen;Dan [3]Peng;Xinhong [1,4]He;Congjian [5]Xu;Xiaojun [5]Chen;Janos [6]LTanyi;Kathleen [7]Montone;Yi [8]Fan;Qihong [9,10,11]Huang;Lin [1,6]Zhang;Xiaomin [3]Zhong 高影响力作者 机构地区：[1]Center for Research on Reproduction and Women’s Health,University of Pennsylvania,Philadelphia,PA 19104,USA;[2]Department of Gynecology and Obstetrics,Key Laboratory of Obstetrics&Gynecologic and Pediatric Diseases and Birth Defects of Ministry of Education,West China Second Hospital,Sichuan University,Chengdu 610041,P.R.China;[3]Key Laboratory for Stem Cells and Tissue Engineering,Ministry of Education,Center for Stem Cell Biology and Tissue Engineering,Department of Biology,Zhongshan School of Medicine,Sun Yat-Sen University,Guangzhou 510080,P.R.China;[4]Beijing Friendship Hospital,Capital Medical University,Beijing 100050,P.R.China;[5]Obstetrics and Gynecology Hospital of Fudan University,Shanghai 200011,P.R.China;[6]Department of Obstetrics and Gynecology,University of Pennsylvania,Philadelphia,PA 19104,USA;[7]Department of Pathology and Laboratory Medicine,University of Pennsylvania,Philadelphia,PA 19104,USA;[8]Department of Radiation Oncology,University of Pennsylvania,Philadelphia,PA 19104,USA;[9]Shanghai Respiratory Research Institute,Shanghai 200032,P.R.China;[10]Department of Pulmonary and Critical Care Medicine,Zhongshan Hospital,Fudan University,Shanghai 200032,P.R.China;[11]Institute of Clinical Science,Zhongshan Hospital,Fudan University,Shanghai 200032,P.R.China高影响力机构 出　　处：《Signal Transduction and Targeted Therapy》索引2018年第3卷第1期,共11页高影响力期刊 基　　金：This work was supported,in whole or in part,by grants from The Science and Technology R&D Program of Chengdu(2015-HM01-00018-SF to X.L.);the Applied Basic Research Programs of Science and Technology Department Foundation of Sichuan Province(2016JY0122 to X.L.);the Key Research Projects of Science and Technology Department Foundation of Sichuan Province(2017SZ0141 to X.L.);the National Key R&D Program of China(2017YFA0105501 to X.Z.);Guangdong Province Science and Technology Project(2015A020212019 to X.Z.),the Basser Center for BRCA(L.Z.);the Harry Fields Professorship(L.Z.),the US National Institutes of Health(R01CA142776 to L.Z.,R01CA190415 to L.Z.,R01CA148759 to Q.H.,and R01NS094533 to Y.F.);the Marsha Rivkin Center for Ovarian Cancer Research(L.Z.).X.L.was supported by the China Scholarship Council. 摘　　要：LIN28B is an evolutionarily conserved RNA-binding protein that regulates mRNA translation and miRNA let-7 maturation in embryonic stem cells and developing tissues.Increasing evidence demonstrates that LIN28B is activated in cancer and serves as a critical oncogene.However,the underlying molecular mechanisms of LIN28B function in tumorigenesis are still largely unknown.Here we report that LIN28B was expressed in over half of the patients with epithelial ovarian cancer who were examined(n=584).Functional experiments demonstrated that LIN28B inhibited ovarian cancer cell apoptosis.Furthermore,we showed that the proapoptotic factor BIM played an essential role in the antiapoptotic function of LIN28B.RNA-IP microarray analysis suggested that LIN28B binds to mRNAs that are associated with the DNA damage pathway,such as AKT2,in ovarian cancer cells.By binding to AKT2 mRNA and enhancing its protein expression,LIN28B regulated FOXO3A protein phosphorylation and decreased the transcriptional level of BIM,which antagonized the antiapoptosis activity of LIN28B.Taken together,these results mechanistically linked LIN28B and the AKT2/FOXO3A/BIM axis to the apoptosis pathway.The findings may have important implications in the diagnosis and therapeutics of ovarian cancer. 关 键 词：AKT2 DIAGNOSIS APOPTOSIS
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