Role of cancer-associated FBXW hotspot mutation in carcinogenesis

2019 Fiscal Year Final Research Report

• 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
• Keywords: 大腸がん

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.

Free Research Field

消化器内科学

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。