title: MYCN-driven regulatory mechanisms controlling LIN28B in neuroblastoma.
abstract: LIN28B has been identified as an oncogene in various tumor entities, including neuroblastoma, a childhood cancer that originates from neural crest-derived cells, and is characterized by amplification of the MYCN oncogene. Recently, elevated LIN28B expression levels were shown to contribute to neuroblastoma tumorigenesis via let-7 dependent de-repression of MYCN. However, additional insight in the regulation of LIN28B in neuroblastoma is lacking. Therefore, we have performed a comprehensive analysis of the regulation of LIN28B in neuroblastoma, with a specific focus on the contribution of miRNAs. We show that MYCN regulates LIN28B expression in neuroblastoma tumors via two distinct parallel mechanisms. First, through an unbiased LIN28B-3'UTR reporter screen, we found that miR-26a-5p and miR-26b-5p regulate LIN28B expression. Next, we demonstrated that MYCN indirectly affects the expression of miR-26a-5p, and hence regulates LIN28B, therefore establishing an MYCN-miR-26a-5p-LIN28B regulatory axis. Second, we provide evidence that MYCN regulates LIN28B expression via interaction with the LIN28B promoter, establishing a direct MYCN-LIN28B regulatory axis. We believe that these findings mark LIN28B as an important effector of the MYCN oncogenic phenotype and underline the importance of MYCN-regulated miRNAs in establishing the MYCN-driven oncogenic process.
authors.affiliation: Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Anneleen
authors.initials: A
authors.lastname: Beckers
authors.affiliation: Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Van Peer
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, PO Box 81, Randwick, NSW 2031, Australia.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Carter
authors.affiliation: Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Moritz
authors.initials: M
authors.lastname: Gartlgruber
authors.affiliation: Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; Institute of Pharmacy and Molecular Biotechnology, and Bioquant Center, University of Heidelberg, Im Neuenheimer Feld 267, Heidelberg 69120, Germany.
authors.forename: Carl
authors.initials: C
authors.lastname: Herrmann
authors.affiliation: Division of Pediatric Hematology-Oncology and Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, 1102 Bates Street, Houston, TX 77030, USA.
authors.forename: Saurabh
authors.initials: S
authors.lastname: Agarwal
authors.affiliation: Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium; Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Hetty H
authors.initials: HH
authors.lastname: Helsmoortel
authors.affiliation: Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany; German Consortium for Translational Cancer Research (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany.
authors.forename: Kristina
authors.initials: K
authors.lastname: Althoff
authors.affiliation: Department of Oncogenomics, Academic Medical Center, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Molenaar
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, PO Box 81, Randwick, NSW 2031, Australia.
authors.forename: Belamy B
authors.initials: BB
authors.lastname: Cheung
authors.affiliation: Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany; Department of Pediatric Oncology and Hematology, University Children's Hospital Essen, Hufelandstr. 55, 45147 Essen, Germany; German Consortium for Translational Cancer Research (DKTK), Partner Site Essen/Duesseldorf, Essen, Germany; Translational Neuro-Oncology, West German Cancer Center (WTZ), University Hospital Essen, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany; Centre for Medical Biotechnology, University Duisburg-Essen, Hufelandstr. 55, 45147 Essen, Germany.
authors.forename: Johannes H
authors.initials: JH
authors.lastname: Schulte
authors.affiliation: Department of Pediatric Hematology-Oncology and Stem Cell Transplantation, Ghent University Hospital, De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Yves
authors.initials: Y
authors.lastname: Benoit
authors.affiliation: Division of Pediatric Hematology-Oncology and Center for Cell and Gene Therapy, Department of Pediatrics, Baylor College of Medicine, 1102 Bates Street, Houston, TX 77030, USA.
authors.forename: Jason M
authors.initials: JM
authors.lastname: Shohet
authors.affiliation: Division of Neuroblastoma Genomics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg 69120, Germany.
authors.forename: Frank
authors.initials: F
authors.lastname: Westermann
authors.affiliation: Children's Cancer Institute Australia for Medical Research, Lowy Cancer Research Centre, UNSW, PO Box 81, Randwick, NSW 2031, Australia.
authors.forename: Glenn M
authors.initials: GM
authors.lastname: Marshall
authors.affiliation: Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Jo
authors.initials: J
authors.lastname: Vandesompele
authors.affiliation: Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium.
authors.forename: Katleen
authors.initials: K
authors.lastname: De Preter
authors.affiliation: Center for Medical Genetics (CMGG), Ghent University, Medical Research Building (MRB1), De Pintelaan 185, 9000 Ghent, Belgium. Electronic address: franki.speleman@ugent.be.
authors.forename: Frank
authors.initials: F
authors.lastname: Speleman
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D035683:MicroRNAs / Q000235:genetics; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000473:pathology*; D009687:Nuclear Proteins / Q000502:physiology*; D015513:Oncogene Proteins / Q000502:physiology*; D016601:RNA-Binding Proteins / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D035683:MicroRNAs; D000071447:N-Myc Proto-Oncogene Protein; D009687:Nuclear Proteins; D015513:Oncogene Proteins; D016601:RNA-Binding Proteins; C516326:LIN28B protein, human; C528163:MIRN26 microRNA, human; C459801:MYCN protein, human
keywords: Cross-species; Integrative analysis; MicroRNA