title: The IGF2 intronic miR-483 selectively enhances transcription from IGF2 fetal promoters and enhances tumorigenesis.
abstract: Insulin-like growth factor 2 (IGF2), a developmentally regulated and maternally imprinted gene, is frequently overexpressed in pediatric cancers. Although loss of imprinting (LOI) at fetal promoters contributes to increased IGF2 in tumors, the magnitude of IGF2 expression suggests the involvement of additional regulatory mechanisms. A microRNA (miRNA) screen of primary Wilms' tumors identified specific overexpression of miR-483-5p, which is embedded within the IGF2 gene. Unexpectedly, the IGF2 mRNA itself is transcriptionally up-regulated by miR-483-5p. A nuclear pool of miR-483-5p binds directly to the 5' untranslated region (UTR) of fetal IGF2 mRNA, enhancing the association of the RNA helicase DHX9 to the IGF2 transcript and promoting IGF2 transcription. Ectopic expression of miR-483-5p in IGF2-dependent sarcoma cells is correlated with increased tumorigenesis in vivo. Together, these observations suggest a functional positive feedback loop of an intronic miRNA on transcription of its host gene.
authors.affiliation: Massachusetts General Hospital Cancer Center, Harvard Medical School, Charlestown, Massachusetts 02129, USA;
authors.forename: Mingzhu
authors.initials: M
authors.lastname: Liu
authors.forename: Anna
authors.initials: A
authors.lastname: Roth
authors.forename: Min
authors.initials: M
authors.lastname: Yu
authors.forename: Robert
authors.initials: R
authors.lastname: Morris
authors.forename: Francesca
authors.initials: F
authors.lastname: Bersani
authors.forename: Miguel N
authors.initials: MN
authors.lastname: Rivera
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Toshihiro
authors.initials: T
authors.lastname: Shioda
authors.forename: Shobha
authors.initials: S
authors.lastname: Vasudevan
authors.forename: Sridhar
authors.initials: S
authors.lastname: Ramaswamy
authors.forename: Shyamala
authors.initials: S
authors.lastname: Maheswaran
authors.forename: Sven
authors.initials: S
authors.lastname: Diederichs
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
mesh_terms: D020121:5' Untranslated Regions / Q000235:genetics; D063646:Carcinogenesis / Q000235:genetics*; D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D053487:DEAD-box RNA Helicases / Q000378:metabolism; D005333:Fetus / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000235:genetics* / Q000378:metabolism; D007438:Introns; D035683:MicroRNAs / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism
chemical_list: D020121:5' Untranslated Regions; C548912:MIRN483 microRNA, human; D035683:MicroRNAs; D009363:Neoplasm Proteins; D012333:RNA, Messenger; D007335:Insulin-Like Growth Factor II; C098487:DHX9 protein, human; D053487:DEAD-box RNA Helicases
keywords: IGF2; fetal promoters; nuclear miRNA; transcription