title: Lin28 promotes transformation and is associated with advanced human malignancies.
abstract: Multiple members of the let-7 family of miRNAs are often repressed in human cancers, thereby promoting oncogenesis by derepressing targets such as HMGA2, K-Ras and c-Myc. However, the mechanism by which let-7 miRNAs are coordinately repressed is unclear. The RNA-binding proteins LIN28 and LIN28B block let-7 precursors from being processed to mature miRNAs, suggesting that their overexpression might promote malignancy through repression of let-7. Here we show that LIN28 and LIN28B are overexpressed in primary human tumors and human cancer cell lines (overall frequency approximately 15%), and that overexpression is linked to repression of let-7 family miRNAs and derepression of let-7 targets. LIN28 and LIN28b facilitate cellular transformation in vitro, and overexpression is associated with advanced disease across multiple tumor types. Our work provides a mechanism for the coordinate repression of let-7 miRNAs observed in a subset of human cancers, and associates activation of LIN28 and LIN28B with poor clinical prognosis.
authors.affiliation: Children's Hospital Boston, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Harvard Stem Cell Institute, Boston, MA, USA.
authors.forename: Srinivas R
authors.initials: SR
authors.lastname: Viswanathan
authors.forename: John T
authors.initials: JT
authors.lastname: Powers
authors.forename: William
authors.initials: W
authors.lastname: Einhorn
authors.forename: Yujin
authors.initials: Y
authors.lastname: Hoshida
authors.forename: Tony L
authors.initials: TL
authors.lastname: Ng
authors.forename: Sara
authors.initials: S
authors.lastname: Toffanin
authors.forename: Maureen
authors.initials: M
authors.lastname: O'Sullivan
authors.forename: Jun
authors.initials: J
authors.lastname: Lu
authors.forename: Letha A
authors.initials: LA
authors.lastname: Phillips
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Lockhart
authors.forename: Samar P
authors.initials: SP
authors.lastname: Shah
authors.forename: Pradeep S
authors.initials: PS
authors.lastname: Tanwar
authors.forename: Craig H
authors.initials: CH
authors.lastname: Mermel
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.forename: Mohammad
authors.initials: M
authors.lastname: Azam
authors.forename: Jose
authors.initials: J
authors.lastname: Teixeira
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Hughes
authors.forename: Josep M
authors.initials: JM
authors.lastname: Llovet
authors.forename: Jerald
authors.initials: J
authors.lastname: Radich
authors.forename: Charles G
authors.initials: CG
authors.lastname: Mullighan
authors.forename: Todd R
authors.initials: TR
authors.lastname: Golub
authors.forename: Poul H
authors.initials: PH
authors.lastname: Sorensen
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000235:genetics; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008113:Liver Neoplasms / Q000235:genetics; D051379:Mice; D035683:MicroRNAs / Q000235:genetics; D009369:Neoplasms / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C516326:LIN28B protein, human; C000715187:Lin28A protein, human; D035683:MicroRNAs; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human