論文

査読有り
2016年8月

ALK(R1275Q) perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN

ONCOGENE
  • T. Ueda
  • ,
  • Y. Nakata
  • ,
  • N. Yamasaki
  • ,
  • H. Oda
  • ,
  • K. Sentani
  • ,
  • A. Kanai
  • ,
  • N. Onishi
  • ,
  • K. Ikeda
  • ,
  • Y. Sera
  • ,
  • Z-i Honda
  • ,
  • K. Tanaka
  • ,
  • M. Sata
  • ,
  • S. Ogawa
  • ,
  • W. Yasui
  • ,
  • H. Saya
  • ,
  • J. Takita
  • ,
  • H. Honda

35
34
開始ページ
4447
終了ページ
4458
記述言語
英語
掲載種別
研究論文(学術雑誌)
DOI
10.1038/onc.2015.519
出版者・発行元
NATURE PUBLISHING GROUP

Overexpression of MYCN is a hallmark of neuroblastoma (NB). ALK(R1275Q), an activating mutation of ALK (anaplastic lymphoma kinase), has been found in sporadic and familial NB patients. In this report, we demonstrated that ALK(R1275Q) knock-in, MYCN transgenic compound mice developed NB with complete penetrance. Transcriptome analysis revealed that ALK(R1275Q) globally downregulated the expression of extracellular matrix (ECM)- and basement membrane (BM)-associated genes in both primary neuronal cells and NB tumors. Accordingly, ALK(R1275Q)/MYCN tumors exhibited reduced expression of ECM/BM-related proteins as compared with MYCN tumors. In addition, on MYCN transduction, ALK(R1275Q)-expressing neuronal cells exhibited increased migratory and invasive activities. Consistently, enhanced invasion and metastasis were demonstrated in ALK(R1275Q)/MYCN mice. These results collectively indicate that ALK(R1275Q) confers a malignant potential on neuronal cells that overexpress MYCN by impairing normal ECM/BM integrity and enhancing tumor growth and dissemination. Moreover, we found that crizotinib, an ALK inhibitor, almost completely inhibited the growth of ALK(R1275Q)/MYCN tumors in an allograft model. Our findings provided insights into the cooperative mechanism of the mutated ALK and overexpressed MYCN in the pathogenesis of NB and demonstrated the effectiveness of crizotinib on ALK(R1275Q)-positive tumors.

Web of Science ® 被引用回数 : 18

リンク情報
DOI
https://doi.org/10.1038/onc.2015.519
Web of Science
https://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=JSTA_CEL&SrcApp=J_Gate_JST&DestLinkType=FullRecord&KeyUT=WOS:000382153100003&DestApp=WOS_CPL
ID情報
  • DOI : 10.1038/onc.2015.519
  • ISSN : 0950-9232
  • eISSN : 1476-5594
  • Web of Science ID : WOS:000382153100003

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