Identification of regulatory components of Wnt signaling in beta-catenin and T-cell factor-4 transcriptional complex as therapeutic targets for colorectal cancer

2019 Fiscal Year Final Research Report

• Project/Area Number: 17H03603
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: National Cancer Center Japan
• Principal Investigator: Masuda Mari 国立研究開発法人国立がん研究センター, 研究所, 主任研究員 (70435717)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: Wntシグナル / TCF4/β-catenin 転写複合体 / プロテオーム解析 / 大腸がん / 治療標的 / がん幹細胞

Outline of Final Research Achievements

Constitutive activation of Wnt signaling is observed in most colorectal cancers (CRCs) and has been believed to play a pivotal role in maintaining cancer stem cells. Through the screening with a siRNA library targeting 70 molecules previously identified as components of the TCF4/β-catenin transcriptional complex, we have explored their regulatory effects on the Wnt signaling. We looked at the expression of Wnt target genes such as c-Myc and Axin, cell proliferation, and Wnt signaling activities in colorectal cancer spheroids by WASA (Wnt signaling Activity in Spheroid Assay) method we developed. As a result, we identified several molecules as candidates for therapeutic targets for CRCs. Of interest, most of the candidate molecules were involved in DNA damage and transcription-coupled DNA repair.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

Wntシグナルの最下流にあるTCF4/β-catenin 転写複合体の制御の全貌を解明することは、多くの生物種において保持されているWntシグナルの機能とその分子機構を理解するうえで学術的意義が高い。一方、Wntシグナルの恒常的活性化は大腸がんをはじめとする様々ながんで報告されており、本シグナル経路に依存する発がんやがん幹細胞の維持に関わる分子機構を理解することによって、新規治療標的の同定に繋がることが期待される。本研究成果は、Wntシグナルの活性化がドライバーとなる様々ながん種に対し新たな治療薬を創出する土台を構築するもので、社会への貢献度が高く重要な意義がある。