• Search Research Projects
  • Search Researchers
  • How to Use
  1. Back to previous page

Role of cancer-associated FBXW hotspot mutation in carcinogenesis

Research Project

Project/Area Number 17K09369
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Research Field Gastroenterology
Research InstitutionThe University of Tokyo

Principal Investigator

Ikenoue Tsuneo  東京大学, 医科学研究所, 准教授 (80396712)

Co-Investigator(Kenkyū-buntansha) 古川 洋一  東京大学, 医科学研究所, 教授 (20272560)
Project Period (FY) 2017-04-01 – 2020-03-31
Project Status Completed (Fiscal Year 2019)
Budget Amount *help
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2019: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
Keywords大腸がん / 大腸腫瘍 / 遺伝子改変マウス / 大腸癌 / FBXW7 / マウスモデル
Outline of Final Research Achievements

To investigate roles of cancer-associated FBXW7 hotspot mutation in colorectal carcinogenesis, we introduced Fbxw7R468C mutation in two mouse models of colorectal cancer. One is a chromosomal instability-related model in which heterozygous Apc deletion is induced using the CDX2P-Cre mice. The other is a microsatellite instability-related model in which homozygous Apc deletion is induced using the CDX2P-polyG-Cre mice. We generated CDX2P-Cre;Apcflox/+;Fbxw7R468C/+ and CDX2P-polyG-Cre;Apcflox/flox;Fbxw7R468C/+ mice. Furthermore, we compared the phenotype of these mice with the counterparts whose Fbxw7 alleles were both wild-type or heterozygously knocked out.
Mice carrying colon-specific Fbxw7R468C/+ allele developed larger number of polyps and showed shorter survival time compared with those carrying colon-specific heterozygous Fbxw7 knockout allele and intact Fbxw7 alleles. These results suggest that Fbxw7R468C mutant has a dominant-negative effect in this context.

Academic Significance and Societal Importance of the Research Achievements

FBXW7変異は大腸癌、胆管癌などで比較的高率に変異を認め、変異はFBXW7の遺伝子配列上の3か所に集中している。FBXW7遺伝子の癌化における働きの研究はほとんどがFBXW7変異を細胞株に導入したり、マウス個体にFBXW7の欠損を導入するという手法を用いており、マウス個体においてヒトの癌で見られるFBXW7変異を導入してその発癌における役割を調べた研究はほとんどない。本研究はマウス個体にヒトで最も高頻度に見られるFBXW7R465C変異(マウスではR468C変異に相当)を導入して発がんへの影響を調べており、FBXW7変異癌の発癌メカニズムの解明、治療法の開発に有益と考えられる。

Report

(4 results)
  • 2019 Annual Research Report   Final Research Report ( PDF )
  • 2018 Research-status Report
  • 2017 Research-status Report
  • Research Products

    (9 results)

All 2019 2018 2017

All Journal Article (7 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 7 results,  Open Access: 6 results,  Acknowledgement Compliant: 1 results) Presentation (2 results)

  • [Journal Article] Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/β-catenin signaling in colorectal cancer cells2019

    • Author(s)
      Ohsugi T, Yamaguchi K, Zhu C, Ikenoue T, Takane K, Shinozaki M, Tsurita G, Yano H, Furukawa Y
    • Journal Title

      Oncogene

      Volume: 38(32) Issue: 32 Pages: 6051-6064

    • DOI

      10.1038/s41388-019-0856-9

    • Related Report
      2019 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Three types of metaplasia model through Kras activation, Pten deletion, or Cdh1 deletion in the gastric epithelium.2019

    • Author(s)
      Kinoshita H, Hayakawa Y, Konishi M, Hata M, Tsuboi M, Hayata Y, Hikiba Y, Ihara S, Nakagawa H, Ikenoue T, Ushiku T, Fukayama M, Hirata Y, Koike K.
    • Journal Title

      Journal of Pathology

      Volume: 247 Issue: 1 Pages: 35-47

    • DOI

      10.1002/path.5163

    • Related Report
      2018 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Establishment and analysis of a novel mouse line carrying a conditional knockin allele of a cancer-specific FBXW7 mutation.2018

    • Author(s)
      Ikenoue T, Terakado Y, Zhu C, Liu X, Ohsugi T, Matsubara D, Fujii T, Kakuta S,Kubo S, Shibata T, Yamaguchi K, Iwakura Y, Furukawa Y.
    • Journal Title

      Sci Rep

      Volume: 8 Issue: 1 Pages: 2021-2021

    • DOI

      10.1038/s41598-018-19769-1

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Decreased expression of interferon-induced protein 2 (IFIT2) by Wnt/β-catenin signaling confers anti-apoptotic properties to colorectal cancer cells.2017

    • Author(s)
      Ohsugi T, Yamaguchi K, Zhu C, Ikenoue T, Furukawa Y.
    • Journal Title

      Oncotarget

      Volume: 8 Issue: 59 Pages: 100176-100186

    • DOI

      10.18632/oncotarget.22122

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Bidirectional reporter assay using HAL promoter and TOPFLASH improves specificity in high-throughput screening of Wnt inhibitors.2017

    • Author(s)
      Yamaguchi K, Zhu C, Ohsugi T, Yamaguchi Y, Ikenoue T, Furukawa Y.
    • Journal Title

      Biotechnology and Bioengineering

      Volume: 114 Issue: 12 Pages: 2868-2882

    • DOI

      10.1002/bit.26394

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Genetic alterations in Japanese extrahepatic biliary tract cancer.2017

    • Author(s)
      Noguchi R, Yamaguchi K, Ikenoue T, Terakado Y, Ohta Y, Yamashita N, Kainuma O, Yokoi S, Maru Y, Nagase H, Furukawa Y.
    • Journal Title

      Oncology Letters

      Volume: 14 Issue: 1 Pages: 877-884

    • DOI

      10.3892/ol.2017.6224

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] FERM domain-containing protein 5 (FRMD5) as a novel target of β-catenin/TCF7L2 complex.2017

    • Author(s)
      Zhu C, Yamaguchi K, Osugi T, Terakado Y, Noguchi R, Ikenoue T, Furukawa Y
    • Journal Title

      Cancer Science

      Volume: 印刷中 Issue: 4 Pages: 612-619

    • DOI

      10.1111/cas.13174

    • Related Report
      2017 Research-status Report
    • Peer Reviewed / Open Access / Acknowledgement Compliant
  • [Presentation] 大腸癌においてWnt/beta-カテニンシグナルはインターフェロン制御因子1(IRF1)を制御する2019

    • Author(s)
      大杉 友之、山口 貴世志、池上 恒雄、高根希世子、篠崎 大、釣田 義一郎、古川洋一
    • Organizer
      第78回日本癌学会学術総会
    • Related Report
      2019 Annual Research Report
  • [Presentation] Context-dependent induction of distinct liver tumors in mice with Kras activation and Pten inactivation2018

    • Author(s)
      池上 恒雄、寺門 侑美、劉 洵、高根 希世子、山口 貴世志、古川洋一
    • Organizer
      第77回日本癌学会学術総会
    • Related Report
      2018 Research-status Report

URL: 

Published: 2017-04-28   Modified: 2021-02-19  

Information User Guide FAQ News Terms of Use Attribution of KAKENHI

Powered by NII kakenhi