2019 Fiscal Year Final Research Report

Elucidation of mechanisms underlying colorectal tumorigenesis associated with deregulation of new Wnt targets

Research Project

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Project/Area Number	17H03575
Research Category	Grant-in-Aid for Scientific Research (B)
Allocation Type	Single-year Grants
Section	一般
Research Field	Tumor biology
Research Institution	The University of Tokyo
Principal Investigator	Furukawa Yoichi 東京大学, 医科学研究所, 教授 (20272560)
Co-Investigator(Kenkyū-buntansha)	山口貴世志東京大学, 医科学研究所, 特任講師 (50466843) 池上恒雄東京大学, 医科学研究所, 准教授 (80396712)
Project Period (FY)	2017-04-01 – 2020-03-31
Keywords	がん / シグナル伝達 / Wnt
Outline of Final Research Achievements	In this study, we identified new target genes regulated by the canonical Wnt signaling. Among the genes, FRMD5 was positively regulated, and IFIT2 was negatively regulated by the signaling. Elevated expression of FRMD5 is associated with invasion of colorectal cancer (CRC) cells, and high FRMD5 expression in CRC tissues is linked to poor prognosis. On the other hand, reduced IFIT2 expression is associated with cell proliferation and resistance to apoptosis. Furthermore, we identified IRF1 as a transcriptional regulator of IFIT2. Importantly, we revealed that activation of the Wnt signaling downregulates IRF1 through its destabilization, and that a deubiquitinating enzyme USP1 plays an important role in the stabilization of IRF1. We also found that UAF1, a USP-interacting protein, is reduced by the activated Wnt signaling. These data suggest that activation of the signaling reduces the stability of IRF1 through its ubiquitination by suppression of USP1-UAF1 activity.
Free Research Field	腫瘍生物学
Academic Significance and Societal Importance of the Research Achievements	本研究成果は大腸がん発生・進展メカニズムの理解に役立つのみならず、新たなバイオマーカーや治療薬開発などに応用できるかもしれない。学術面では、Wnt活性化により特定のタンパク質分解が誘導されるという発見は、これまで知られていない新たなWntシグナル制御機構で、他にも制御される分子が存在する可能性が考えられる。社会的意義ではFRMD5の発現と臨床情報の詳細な検討により、FRMD5が新規予後マーカーとして利用できる可能性が示された。またWnt阻害によって発現が増加するIFIT2やIRF1は、Wntを阻害する化合物、抗体等の探索プローブとしての応用が可能であり、今後の治療薬開発に役立つかもしれない。