オダ ヒデアキ   ODA Hideaki
  小田 秀明
   所属   医学部 医学科
   職種   教授・講座主任
論文種別 原著
言語種別 英語
査読の有無 査読あり
表題 ALK(R1275Q) perturbs extracellular matrix, enhances cell invasion and leads to the development of neuroblastoma in cooperation with MYCN.
掲載誌名 正式名:Oncogene
略  称:Oncogene
ISSNコード:(1476-5594)0950-9232(Linking)
掲載区分国外
巻・号・頁 35(34),4447-58頁
著者・共著者 Ueda T, Nakata Y, Yamasaki N, Oda H, Sentani K, Kanai A, Onishi N, Ikeda K, Sera Y, Honda Z-I, Tanaka K, Sata M, Ogawa S, Yasui W, Saya H, Takita J, Honda H
発行年月 2016/08
概要 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.
DOI 10.1038/onc.2015.519
PMID 26829053