Role of cancer-associated FBXW hotspot mutation in carcinogenesis

• Project/Area Number: 17K09369
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The 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: ¥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。

Research Products

• [Journal Article] Anti-apoptotic effect by the suppression of IRF1 as a downstream of Wnt/β-catenin signaling in colorectal cancer cells (2019)
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
  • 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
• [Presentation] Context-dependent induction of distinct liver tumors in mice with Kras activation and Pten inactivation (2018)
  • 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