RRC ID 44203
Author Kishida S, Mu P, Miyakawa S, Fujiwara M, Abe T, Sakamoto K, Onishi A, Nakamura Y, Kadomatsu K.
Title Midkine promotes neuroblastoma through Notch2 signaling.
Journal Cancer Res
Abstract Midkine is a heparin-binding growth factor highly expressed in various cancers, including neuroblastoma, the most common extracranial pediatric solid tumor. Prognosis of patients with neuroblastoma in which MYCN is amplified remains particularly poor. In this study, we used a MYCN transgenic model for neuroblastoma in which midkine is highly expressed in precancerous lesions of sympathetic ganglia. Genetic ablation of midkine in this model delayed tumor formation and reduced tumor incidence. Furthermore, an RNA aptamer that specifically bound midkine suppressed the growth of neuroblastoma cells in vitro and in vivo in tumor xenografts. In precancerous lesions, midkine-deficient MYCN transgenic mice exhibited defects in activation of Notch2, a candidate midkine receptor, and expression of the Notch target gene HES1. Similarly, RNA aptamer-treated tumor xenografts also showed attenuation of Notch2-HES1 signaling. Our findings establish a critical role for the midkine-Notch2 signaling axis in neuroblastoma tumorigenesis, which implicates new strategies to treat neuroblastoma.
Volume 73(4)
Pages 1318-27
Published 2013-2-15
DOI 10.1158/0008-5472.CAN-12-3070
PII 0008-5472.CAN-12-3070
PMID 23243020
MeSH Animals Aptamers, Nucleotide / genetics Aptamers, Nucleotide / metabolism Aptamers, Nucleotide / pharmacology Blotting, Western Cell Line, Tumor Cytokines / genetics* Cytokines / metabolism Ganglia, Sympathetic / metabolism Ganglia, Sympathetic / pathology Gene Expression Regulation, Neoplastic HEK293 Cells Humans Immunohistochemistry Mice Mice, 129 Strain Mice, Knockout Mice, Nude Mice, Transgenic Midkine Neuroblastoma / genetics* Neuroblastoma / pathology Neuroblastoma / prevention & control Protein Binding Proto-Oncogene Proteins c-myc / genetics Proto-Oncogene Proteins c-myc / metabolism Receptor, Notch2 / genetics* Receptor, Notch2 / metabolism Reverse Transcriptase Polymerase Chain Reaction Signal Transduction* Xenograft Model Antitumor Assays
IF 9.727
Times Cited 28
Human and Animal Cells LNCap.FGC(RCB2144)