Authors' Affiliations: Sonia and Arthur Labatt Brain Tumor Research Centre, Division of Hematology-Oncology, Division of Neurosurgery, and Department of Pathology, Hospital for Sick Children; Departments of Laboratory Medicine and Pathobiology and Medical Biophysics, University of Toronto; Division of Applied Molecular Oncology, University Health Network, Toronto, Ontario, Canada; Department of Pediatric Hematology/Oncology, Case Western Reserve University School of Medicine, Rainbow Babies and Children's Hospital/Ireland Cancer Center, Cleveland, Ohio; and Department of Neurosurgery, Asan Medical Center, University of Ulsan, Seoul, Korea.
Cancer Res. 2010 Sep 28.
Mechanisms by which c-Myc (Myc) amplification confers aggressive medulloblastoma phenotypes are poorly defined. Here, we show using orthotopic models that high Myc expression promotes cell migration/invasion and induces metastatic tumors, which recapitulate aggressive histologic features of Myc-amplified primary human medulloblastoma. Using ChIP-chip analysis, we identified cell migration and adhesion genes, including Tsp-1/THBS1, ING4, PVRL3, and PPAP2B, as Myc-bound loci in medulloblastoma cells. Expression of Tsp-1 was most consistently and robustly diminished in medulloblastoma cell lines and primary human tumors with high Myc expression (n = 101, P = 0.032). Strikingly, stable Tsp-1 expression significantly attenuated in vitro transformation and invasive/migratory properties of high Myc-expressing medulloblastoma cells without altering cell proliferation, whereas RNA interference-mediated Myc knockdown was consistently accompanied by increased Tsp-1 levels and reduced cell migration and invasion in medulloblastoma cells. Chromatin immunoprecipitation (ChIP) assays revealed colocalization of Myc and obligate partner Max and correlated diminished RNA polymerase II occupancy (~3-fold decrease, P < 0.01) with increased Myc binding at a core Tsp-1 promoter. Reporter gene and/or gel shift assays confirmed direct repression of Tsp-1 transcription by Myc and also identified JPO2, a Myc interactor associated with metastatic medulloblastoma, as a cofactor in Myc-mediated Tsp-1 repression. These findings indicate the Myc-regulatory network targets Tsp-1 via multiple mechanisms in medulloblastoma transformation, and highlight a novel critical role for Tsp-1 in Myc-mediated aggressive medulloblastoma phenotypes. Cancer Res; 70(20); OF1-12.©2010 AACR.
PMID: 20876797 [PubMed - as supplied by publisher] Source: National Library of Medicine.
