title: Oncofetal protein IGF2BP3 facilitates the activity of proto-oncogene protein eIF4E through the destabilization of EIF4E-BP2 mRNA.
abstract: RNA-binding proteins (RBPs) have important roles in tumorigenesis. Although IGF2BP3, an evolutionally conserved RBP, has been reported as a useful diagnostic marker for various cancers and has been considered a regulator of tumorigenesis, little is known of the function of IGF2BP3 because of lack of information regarding IGF2BP3 target mRNAs. Here, we report the identification of IGF2BP3 target mRNAs and IGF2BP3 function in cancer proliferation. We identified mRNAs with altered expression in IGF2BP3-depleted cells by massive sequencing analysis and IGF2BP3-binding RNAs by immunoprecipitation of IGF2BP3 followed by massive sequencing analysis, resulting in the identification of 110 candidates that are negatively regulated by IGF2BP3. We found that IGF2BP3 destabilized EIF4E-BP2 and MEIS3 mRNAs. Co-immunoprecipitation analysis revealed the interaction between IGF2BP3 and ribonucleases such as XRN2 and exosome component. The retarded proliferation of IGF2BP3-depleted cells was partially rescued by the depletion of EIF4E-BP2, which negatively regulates eukaryotic translation initiation factor 4E (eIF4E), an activator of translation and a well-known proto-oncogene. Consistent with this observation, IGF2BP3 depletion reduced phosphorylated eIF4E, the active form, and translational efficiency of eIF4E target transcripts. Reduction of phosphorylated eIF4E by IGF2BP3 depletion was rescued by EIF4E-BP2 depletion. At last, we found an inverse correlation between the expression level of IGF2BP3 and EIF4E-BP2 in human lung adenocarcinoma tissues. Together, these results suggest that IGF2BP3 promotes eIF4E-mediated translational activation through the reduction of EIF4E-BP2 via mRNA degradation, leading to enhanced cell proliferation. This is the first report demonstrating that IGF2BP3 is an RNA-destabilizing factor. Notably, here we provide the first evidence for the functional linkage between two previously well-known cancer biomarkers, IGF2BP3 and eIF4E.
authors.affiliation: Isotope Science Center, The University of Tokyo, Tokyo, Japan.
authors.forename: R
authors.initials: R
authors.lastname: Mizutani
authors.affiliation: Isotope Science Center, The University of Tokyo, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Imamachi
authors.affiliation: Department of Pathology, Asahi General Hospital, Chiba, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Department of Pathology, Asahi General Hospital, Chiba, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Yoshida
authors.affiliation: Department of Pathology, Asahi General Hospital, Chiba, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Tochigi
authors.affiliation: Medical Consultation Office, Incorporated, Yokohama, Japan.
authors.forename: T
authors.initials: T
authors.lastname: Oonishi
authors.affiliation: Department of Computational Biology, Graduate School of Frontier Sciences, The University of Tokyo, Kashiwa, Japan.
authors.forename: Y
authors.initials: Y
authors.lastname: Suzuki
authors.affiliation: Isotope Science Center, The University of Tokyo, Tokyo, Japan.
authors.forename: N
authors.initials: N
authors.lastname: Akimitsu
mesh_terms: D000072283:A549 Cells; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D049109:Cell Proliferation / Q000235:genetics; D039561:Eukaryotic Initiation Factor-4E / Q000235:genetics / Q000378:metabolism*; D039642:Eukaryotic Initiation Factors / Q000235:genetics / Q000378:metabolism*; D005095:Exoribonucleases / Q000378:metabolism; D015870:Gene Expression; D006367:HeLa Cells; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism; D011485:Protein Binding; D000090063:Proto-Oncogene Mas; D034622:RNA Interference; D020871:RNA Stability / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism*; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C104151:EIF4EBP2 protein, human; D039561:Eukaryotic Initiation Factor-4E; D039642:Eukaryotic Initiation Factors; C498780:IGF2BP3 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D005095:Exoribonucleases; C120903:XRN2 protein, human