ALK is a MYCN target gene and regulates cell migration and invasion in neuroblastoma

Md Kamrul Hasan; Asmaa Nafady; Atsushi Takatori; Satoshi Kishida; Miki Ohira; Yusuke Suenaga; Shamim Hossain; Jesmin Akter; Atsushi Ogura; Yohko Nakamura; Kenji Kadomatsu; Akira Nakagawara

doi:10.1038/srep03450

ALK is a MYCN target gene and regulates cell migration and invasion in neuroblastoma

Sci Rep. 2013 Dec 20:3:3450. doi: 10.1038/srep03450.

Authors

Affiliations

¹ 1] Division of Biochemistry & Innovative Cancer Therapeutics, and Children's Cancer Research Center, Chiba Cancer Center, Chiba, Japan [2] Department of Molecular Biology and Oncology, Chiba University Graduate School of Medicine, Chiba, Japan [3].
² 1] Division of Biochemistry & Innovative Cancer Therapeutics, and Children's Cancer Research Center, Chiba Cancer Center, Chiba, Japan [2] Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt; Department of Molecular Biology and Oncology, Chiba University Graduate School of Medicine, Chiba, Japan [3].
³ Division of Biochemistry & Innovative Cancer Therapeutics, and Children's Cancer Research Center, Chiba Cancer Center, Chiba, Japan.
⁴ Department of Biochemistry, Nagoya University Graduate School of Medicine, Nagoya, Japan.
⁵ Division of Cancer Genomics, Chiba Cancer Center Research Institute, Chiba, Japan.
⁶ 1] Division of Biochemistry & Innovative Cancer Therapeutics, and Children's Cancer Research Center, Chiba Cancer Center, Chiba, Japan [2] Department of Molecular Biology and Oncology, Chiba University Graduate School of Medicine, Chiba, Japan.

Abstract

Human anaplastic lymphoma kinase (ALK) has been identified as an oncogene that is mutated or amplified in NBLs. To obtain a better understanding of the molecular events associated with ALK in the pathogenesis of NBL, it is necessary to clarify how ALK gene contributes to NBL progression. In the present study, we found that ALK expression was significantly high in NBL clinical samples with amplified MYCN (n = 126, P < 0.01) and in developing tumors of MYCN-transgenic mice. Indeed, promoter analysis revealed that ALK is a direct transcriptional target of MYCN. Overexpression and knockdown of ALK demonstrated its function in cell proliferation, migration and invasion. Moreover, treatment with an ALK inhibitor, TAE-684, efficiently suppressed such biological effects in MYCN amplified cells and tumor growth of the xenograft in mice. Our present findings explore the fundamental understanding of ALK in order to develop novel therapeutic tools by targeting ALK for aggressive NBL treatment.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anaplastic Lymphoma Kinase
Animals
Cell Movement / genetics
Cell Proliferation
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Disease Models, Animal
Gene Amplification
Gene Expression Regulation, Neoplastic
Heterografts
Humans
Mice
N-Myc Proto-Oncogene Protein
Neoplasm Invasiveness
Neuroblastoma / genetics*
Neuroblastoma / metabolism*
Neuroblastoma / pathology
Nuclear Proteins / genetics
Nuclear Proteins / metabolism*
Oncogene Proteins / genetics
Oncogene Proteins / metabolism*
Oncogenes
Protein Binding
Protein Kinase Inhibitors / pharmacology
Proto-Oncogene Proteins c-myc / genetics
Proto-Oncogene Proteins c-myc / metabolism
RNA, Messenger / genetics
Receptor Protein-Tyrosine Kinases / antagonists & inhibitors
Receptor Protein-Tyrosine Kinases / genetics*
Receptor Protein-Tyrosine Kinases / metabolism

Substances

MYCN protein, human
N-Myc Proto-Oncogene Protein
Nuclear Proteins
Oncogene Proteins
Protein Kinase Inhibitors
Proto-Oncogene Proteins c-myc
RNA, Messenger
ALK protein, human
Alk protein, mouse
Anaplastic Lymphoma Kinase
Receptor Protein-Tyrosine Kinases