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 activ...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.展开更多
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.)+4 种基金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.
文摘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.
