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Cancer Cell. 2017 Sep 11;32(3):310-323.e5. doi: 10.1016/j.ccell.2017.08.002. Epub 2017 Aug 31.

LMO1 Synergizes with MYCN to Promote Neuroblastoma Initiation and Metastasis.

Author information

1
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, MN 55902, USA. Electronic address: zhu.shizhen@mayo.edu.
2
Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine, Mayo Clinic Cancer Center, Rochester, MN 55902, USA.
3
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
4
Department of Molecular Pharmacology & Experimental Therapeutics, Center for Individualized Medicine, Mayo Clinic College of Medicine, Rochester, MN 55902, USA.
5
Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, Philadelphia, PA 19104, USA.
6
Department of Molecular Medicine, University of Auckland, Auckland, New Zealand.
7
Departments of Oncology, Radiation Oncology, and Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN 55902, USA.
8
Department of Pathology, Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
9
Department of Biostatistics and Computational Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA.
10
Department of Dermatology, Mayo Clinic, Rochester, MN 55902, USA.
11
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 at the University of Pennsylvania, Philadelphia, PA 19104, USA; Abramson Family Cancer Research Institute, Philadelphia, PA 19104, USA.
12
Department of Pediatric Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. Electronic address: thomas_look@dfci.harvard.edu.

Abstract

A genome-wide association study identified LMO1, which encodes an LIM-domain-only transcriptional cofactor, as a neuroblastoma susceptibility gene that functions as an oncogene in high-risk neuroblastoma. Here we show that dβh promoter-mediated expression of LMO1 in zebrafish synergizes with MYCN to increase the proliferation of hyperplastic sympathoadrenal precursor cells, leading to a reduced latency and increased penetrance of neuroblastomagenesis. The transgenic expression of LMO1 also promoted hematogenous dissemination and distant metastasis, which was linked to neuroblastoma cell invasion and migration, and elevated expression levels of genes affecting tumor cell-extracellular matrix interaction, including loxl3, itga2b, itga3, and itga5. Our results provide in vivo validation of LMO1 as an important oncogene that promotes neuroblastoma initiation, progression, and widespread metastatic dissemination.

KEYWORDS:

ECM; LMO1; MYCN; metastasis; neuroblastoma; tumorigenesis; zebrafish model

PMID:
28867147
PMCID:
PMC5605802
DOI:
10.1016/j.ccell.2017.08.002
[Indexed for MEDLINE]
Free PMC Article

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