title: Lin28b is sufficient to drive liver cancer and necessary for its maintenance in murine models.
abstract: Lin28a/b are RNA-binding proteins that influence stem cell maintenance, metabolism, and oncogenesis. Poorly differentiated, aggressive cancers often overexpress Lin28, but its role in tumor initiation or maintenance has not been definitively addressed. We report that LIN28B overexpression is sufficient to initiate hepatoblastoma and hepatocellular carcinoma in murine models. We also detected Lin28b overexpression in MYC-driven hepatoblastomas, and liver-specific deletion of Lin28a/b reduced tumor burden, extended latency, and prolonged survival. Both intravenous siRNA against Lin28b and conditional Lin28b deletion reduced tumor burden and prolonged survival. Igf2bp proteins are upregulated, and Igf2bp3 is required in the context of LIN28B overexpression to promote growth. Therefore, multiple murine models demonstrate that Lin28b is both sufficient to initiate liver cancer and necessary for its maintenance.
authors.affiliation: Children's Research Institute, Departments of Pediatrics and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Liem H
authors.initials: LH
authors.lastname: Nguyen
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital Boston, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Daisy A
authors.initials: DA
authors.lastname: Robinton
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital Boston, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Marc T
authors.initials: MT
authors.lastname: Seligson
authors.affiliation: Children's Research Institute, Departments of Pediatrics and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA; Organ Transplant Center, First Affiliated Hospital of Sun Yat-Sen University, Guangzhou, 510080, China.
authors.forename: Linwei
authors.initials: L
authors.lastname: Wu
authors.affiliation: Children's Research Institute, Departments of Pediatrics and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Departments of Pathology and Pediatrics, Children's Medical Center and University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Dinesh
authors.initials: D
authors.lastname: Rakheja
authors.affiliation: Department of Molecular Genetics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Comerford
authors.affiliation: Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Saleh
authors.initials: S
authors.lastname: Ramezani
authors.affiliation: Department of Radiology and Advanced Imaging Research Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Xiankai
authors.initials: X
authors.lastname: Sun
authors.affiliation: Children's Research Institute, Departments of Pediatrics and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Monisha S
authors.initials: MS
authors.lastname: Parikh
authors.affiliation: Children's Research Institute, Departments of Pediatrics and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Erin H
authors.initials: EH
authors.lastname: Yang
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital Boston, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: John T
authors.initials: JT
authors.lastname: Powers
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital Boston, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Gen
authors.initials: G
authors.lastname: Shinoda
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital Boston, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA.
authors.forename: Samar P
authors.initials: SP
authors.lastname: Shah
authors.affiliation: Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hammer
authors.affiliation: Division of Pediatric Hematology/Oncology, Children's Hospital Boston, Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA 02115, USA. Electronic address: george.daley@childrens.harvard.edu.
authors.forename: George Q
authors.initials: GQ
authors.lastname: Daley
authors.affiliation: Children's Research Institute, Departments of Pediatrics and Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA. Electronic address: hao.zhu@utsouthwestern.edu.
authors.forename: Hao
authors.initials: H
authors.lastname: Zhu
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000378:metabolism*; D018197:Hepatoblastoma / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D008114:Liver Neoplasms, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009857:Oncogenes; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000378:metabolism / Q000502:physiology*; D047368:Tumor Burden
chemical_list: C498780:IGF2BP3 protein, human; C516326:LIN28B protein, human; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D016601:RNA-Binding Proteins