國家衛生研究院 NHRI:Item 3990099045/10837
English  |  正體中文  |  简体中文  |  全文笔数/总笔数 : 12145/12927 (94%)
造访人次 : 925850      在线人数 : 602
RC Version 6.0 © Powered By DSPACE, MIT. Enhanced by NTU Library IR team.
搜寻范围 查询小技巧：
  • 您可在西文检索词汇前后加上"双引号"，以获取较精准的检索结果
  • 若欲以作者姓名搜寻，建议至进阶搜寻限定作者字段，可获得较完整数据
    •  进阶搜寻
    主页 ‧ 登入 ‧ 上传 ‧ 说明 ‧ 关于NHRI ‧ 管理 到手机版


    jsp.display-item.identifier=請使用永久網址來引用或連結此文件: http://ir.nhri.org.tw/handle/3990099045/10837


    题名: Mutant KIT translocates into the nucleus and induces NFKBIB expression that leads to KIT expression in imatinib-resistant gastrointestinal stromal tumors
    作者: Hsueh, YS;Chang, HH;Shan, YS;Sun, HS;Fletcher, JA;Li, CF;Chen, LT
    贡献者: National Institute of Cancer Research
    摘要: Background: Gastrointestinal stromal tumor (GIST) is a dominantly mutant KIT-driven tumor. Prolonged tyrosine kinase inhibitor (TKI) treatment may result in a resistant phenotype through acquired secondary KIT mutation. Increasing evidences show that membrane-bound receptors, as EGFR, can translocate into the nucleus, mediate genes expression, and lead to tumor survival and drug resistance. However, it’s barely known the nuclear role of KIT in GIST. Methods: In this study, two imatinib (IM)-resistant GIST cell lines, GIST48 and GIST430, were used as a model. Results: In this study, we first showed that KIT is distributed both in the cytoplasm and the nucleus in IM-resistant GIST cells. Using ChIP-seq and ChIP assay, we identified that nuclear KIT bound to the NFKBIB promoter region and regulated its expression. The expression levels of NFKBIB and phosopho-KIT were significantly correlated with NCCN-risk category in surgically resected GISTs stained by immunohistochemistry. The cell viabilities were inhibited as accompanying with KIT reduction in GIST cells while NFKBIB was silenced or RELA was overexpressed. Moreover, RELA was activated, translocated into the nucleus, and bound to KIT promoter region in NFKBIB-silenced or RELA-overexpressed GIST cells. Valproic acid, acted as a NFKB inducer, could induce RELA nucleus translocation and binding to KIT promoter region that led to the reduction of protein and RNA expression level of KIT and the cell viabilities of GIST cells. Furthermore, the combination of IM with low-dose valproic acid showed synergistically inhibitory effect on cell viabilities of GIST cells and comparable effects on reducing phospho-KIT level and inhibiting tumor growth as high-dose valproic acid did in GIST430 xenograft model. Conclusions: Taken together, we first demonstrated that phosphorylated KIT could translocate into the nucleus and drive itself expression in IM-resistant GIST cells through mediating NFKBIB expression. In addition, our findings identified a novel and druggable KIT-NFKBIB-NFKB regulatory axis that provides a new insight on tumorigenesis and therapeutic option for IM-resistant, mutant KIT-expressing GISTs.
    日期: 2017-09
    關聯: Annals of Oncology. 2017 Sep;28(Suppl. 5):Meeting Abstract 1679P.
    Link to: https://doi.org/10.1093/annonc/mdx390.051
    JIF/Ranking 2023: http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=0923-7534&DestApp=IC2JCR
    Cited Times(WOS): https://www.webofscience.com/wos/woscc/full-record/WOS:000411324004194
    显示于类别:[陳立宗] 會議論文/會議摘要

    文件中的档案:

    档案 描述 大小格式浏览次数
    ISI000411324004194.pdf66KbAdobe PDF180检视/开启


    在NHRI中所有的数据项都受到原著作权保护.

    TAIR相关文章

    DSpace Software Copyright © 2002-2004  MIT &  Hewlett-Packard  /   Enhanced by   NTU Library IR team Copyright ©   - 回馈