A LIN28B-RAN-AURKA Signaling Network Promotes Neuroblastoma Tumorigenesis.
A more complete understanding of aberrant oncogenic signaling in neuroblastoma, a malignancy of the developing sympathetic nervous system, is paramount to improving patient outcomes. Recently, we identified LIN28B as an oncogenic driver in high-risk neuroblastoma. Here, we identify the oncogene RAN as a LIN28B target and show regional gain of chromosome 12q24 as an additional somatic alteration resulting in increased RAN expression. We show that LIN28B influences RAN expression by promoting RAN Binding Protein 2 expression and by directly binding RAN mRNA. Further, we demonstrate a convergence of LIN28B and RAN signaling on Aurora kinase A activity. Collectively, these findings demonstrate that LIN28B-RAN-AURKA signaling drives neuroblastoma oncogenesis, suggesting that this pathway may be amenable to therapeutic targeting.
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Robert W
RW
Schnepp
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Priya
P
Khurana
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Edward F
EF
Attiyeh
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Biomedical and Health Informatics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Pichai
P
Raman
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Sara E
SE
Chodosh
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Derek A
DA
Oldridge
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Maria E
ME
Gagliardi
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
Karina L
KL
Conkrite
Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Shahab
S
Asgharzadeh
Division of Hematology, Oncology, and Blood and Marrow Transplantation, Department of Pediatrics, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
Robert C
RC
Seeger
Division of Gastroenterology, Washington University School of Medicine in St. Louis, St. Louis, MO 63110, USA.
Blair B
BB
Madison
Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Division of Gastroenterology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Department of Genetics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA.
Anil K
AK
Rustgi
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: maris@email.chop.edu.
John M
JM
Maris
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA; Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Perelman School of Medicine at University of Pennsylvania, Philadelphia, PA 19104, USA. Electronic address: diskin@email.chop.edu.
Sharon J
SJ
Diskin
D064096:Aurora Kinase A / Q000235:genetics* / Q000378:metabolism; D015153:Blotting, Western; D063646:Carcinogenesis / Q000235:genetics; D045744:Cell Line, Tumor; D002648:Child; D002881:Chromosomes, Human, Pair 12 / Q000235:genetics; D056915:DNA Copy Number Variations; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D053208:Kaplan-Meier Estimate; D035683:MicroRNAs / Q000235:genetics; D018832:Molecular Chaperones / Q000235:genetics / Q000378:metabolism; D000071447:N-Myc Proto-Oncogene Protein; D009447:Neuroblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D028861:Nuclear Pore Complex Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D020411:Oligonucleotide Array Sequence Analysis; D015513:Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000235:genetics*; D020931:ran GTP-Binding Protein / Q000235:genetics* / Q000378:metabolism
C516326:LIN28B protein, human; C459801:MYCN protein, human; D035683:MicroRNAs; D018832:Molecular Chaperones; D000071447:N-Myc Proto-Oncogene Protein; D028861:Nuclear Pore Complex Proteins; D009687:Nuclear Proteins; D015513:Oncogene Proteins; C120587:RAN protein, human; D016601:RNA-Binding Proteins; C487931:mirnlet7 microRNA, human; C094493:ran-binding protein 2; C576917:AURKA protein, human; D064096:Aurora Kinase A; D020931:ran GTP-Binding Protein