A LIN28B-RAN-AURKA Signaling Network Promotes Neuroblastoma Tumorigenesis

Cancer Cell. 2015 Nov 9;28(5):599-609. doi: 10.1016/j.ccell.2015.09.012. Epub 2015 Oct 17.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aurora Kinase A / genetics*
  • Aurora Kinase A / metabolism
  • Blotting, Western
  • Carcinogenesis / genetics
  • Cell Line, Tumor
  • Child
  • Chromosomes, Human, Pair 12 / genetics
  • DNA Copy Number Variations
  • Gene Amplification
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Kaplan-Meier Estimate
  • MicroRNAs / genetics
  • Molecular Chaperones / genetics
  • Molecular Chaperones / metabolism
  • N-Myc Proto-Oncogene Protein
  • Neuroblastoma / genetics*
  • Neuroblastoma / metabolism
  • Neuroblastoma / pathology
  • Nuclear Pore Complex Proteins / genetics
  • Nuclear Pore Complex Proteins / metabolism
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Oncogene Proteins / genetics
  • Oncogene Proteins / metabolism
  • RNA-Binding Proteins / genetics*
  • RNA-Binding Proteins / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction / genetics*
  • ran GTP-Binding Protein / genetics*
  • ran GTP-Binding Protein / metabolism

Substances

  • LIN28B protein, human
  • MYCN protein, human
  • MicroRNAs
  • Molecular Chaperones
  • N-Myc Proto-Oncogene Protein
  • Nuclear Pore Complex Proteins
  • Nuclear Proteins
  • Oncogene Proteins
  • RAN protein, human
  • RNA-Binding Proteins
  • mirnlet7 microRNA, human
  • ran-binding protein 2
  • AURKA protein, human
  • Aurora Kinase A
  • ran GTP-Binding Protein