title: Multiple mechanisms disrupt the let-7 microRNA family in neuroblastoma.
abstract: Poor prognosis in neuroblastoma is associated with genetic amplification of MYCN. MYCN is itself a target of let-7, a tumour suppressor family of microRNAs implicated in numerous cancers. LIN28B, an inhibitor of let-7 biogenesis, is overexpressed in neuroblastoma and has been reported to regulate MYCN. Here we show, however, that LIN28B is dispensable in MYCN-amplified neuroblastoma cell lines, despite de-repression of let-7. We further demonstrate that MYCN messenger RNA levels in amplified disease are exceptionally high and sufficient to sponge let-7, which reconciles the dispensability of LIN28B. We found that genetic loss of let-7 is common in neuroblastoma, inversely associated with MYCN amplification, and independently associated with poor outcomes, providing a rationale for chromosomal loss patterns in neuroblastoma. We propose that let-7 disruption by LIN28B, MYCN sponging, or genetic loss is a unifying mechanism of neuroblastoma development with broad implications for cancer pathogenesis.
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Powers
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Kaloyan M
authors.initials: KM
authors.lastname: Tsanov
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Daniel S
authors.initials: DS
authors.lastname: Pearson
authors.affiliation: Department of Pediatric Oncology, University Hospital Köln, Köln 50937, Germany.
authors.forename: Frederik
authors.initials: F
authors.lastname: Roels
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts 02115, USA.
authors.forename: Catherine S
authors.initials: CS
authors.lastname: Spina
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Ebright
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Seligson
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Yvanka
authors.initials: Y
authors.lastname: de Soysa
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Patrick
authors.initials: P
authors.lastname: Cahan
authors.affiliation: Department of Pediatric Oncology, University Hospital Köln, Köln 50937, Germany.
authors.forename: Jessica
authors.initials: J
authors.lastname: Theißen
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Ho-Chou
authors.initials: HC
authors.lastname: Tu
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Areum
authors.initials: A
authors.lastname: Han
authors.affiliation: Department of Pathology, Boston Children's Hospital, Boston Massachusetts 02215, USA.
authors.forename: Kyle C
authors.initials: KC
authors.lastname: Kurek
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Grace S
authors.initials: GS
authors.lastname: LaPier
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Jihan K
authors.initials: JK
authors.lastname: Osborne
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Samantha J
authors.initials: SJ
authors.lastname: Ross
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.
authors.forename: Marcella
authors.initials: M
authors.lastname: Cesana
authors.affiliation: Wyss Institute for Biologically Inspired Engineering, Boston, Massachusetts 02115, USA.|Department of Biological Engineering, Massachusetts Institute of Technology, Broad Institute of MIT and Harvard, Cambridge, Massachusetts 02142, USA.
authors.forename: James J
authors.initials: JJ
authors.lastname: Collins
authors.affiliation: Department of Pediatric Oncology, University Hospital Köln, Köln 50937, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Berthold
authors.affiliation: Division of Pediatric Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts 02115, USA.|Stem Cell Transplantation Program, Dana Farber Cancer Institute &Boston Children's Hospital, Boston, Massachusetts 02115, USA.|Department of Biological Chemistry &Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts 02115, USA.|Harvard Stem Cell Institute, Cambridge, Massachusetts 02138, USA.
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D002872:Chromosome Deletion; D005260:Female; D005784:Gene Amplification / Q000235:genetics*; D017353:Gene Deletion; D052138:Genes, Neoplasm / Q000235:genetics; D006801:Humans; D051379:Mice; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008957:Models, Genetic; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D015513:Oncogene Proteins / Q000235:genetics*; D016601:RNA-Binding Proteins / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020413:3' Untranslated Regions; C516326:LIN28B protein, human; C459801:MYCN protein, human; D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human