Identification of regulatory components of Wnt signaling in beta-catenin and T-cell factor-4 transcriptional complex as therapeutic targets for colorectal cancer
| Project/Area Number |
17H03603
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Tumor therapeutics
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| Research Institution | National Cancer Center Japan |
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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)
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| Project Period (FY) |
2017-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥18,070,000 (Direct Cost: ¥13,900,000、Indirect Cost: ¥4,170,000)
Fiscal Year 2019: ¥3,640,000 (Direct Cost: ¥2,800,000、Indirect Cost: ¥840,000)
Fiscal Year 2018: ¥7,540,000 (Direct Cost: ¥5,800,000、Indirect Cost: ¥1,740,000)
Fiscal Year 2017: ¥6,890,000 (Direct Cost: ¥5,300,000、Indirect Cost: ¥1,590,000)
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| 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 / Wnt シグナル / TCF4 / β-catenin / 転写複合体 / 分子標的治療薬 / トランスレーショナルリサーチ / 細胞・組織 / 癌 / 発現制御 / シグナル伝達 |
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| 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.
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| 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。
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Report
(4 results)
Research Products
(39 results)
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[Journal Article] Prognostic impact of ACTN4 gene copy number alteration in hormone receptor-positive, HER2-negative, node-negative invasive breast carcinoma2020
Author(s)
Sugano T, Yoshida M, Masuda M, Ono M, Tamura K, Kinoshita T, Tsuda H, Honda K, Gemma A, Yamada T
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Journal Title
Br J Cancer.
Volume: 122
Issue: 12
Pages: 1811-1817
DOI
Related Report
Peer Reviewed
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[Presentation] TRAF2 and NCK-interacting protein kinase (TNIK) regulates cancer stemness and adipogenesis of osteosarcoma cells.2018
Author(s)
T. Hirozane, M. Masuda, N. Goto, T. Sugano, N. Asano, E. Kobayashi, K. Horiuchi, H. Morioka, A. Kawai, M. Sawa, M. Matsumoto, M. Nakamura, T. Yamada.
Organizer
AACR Annual meeting 2018
Related Report
Int'l Joint Research
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[Presentation] TNIK is a novel molecular target for osteosarcoma treatment and controls osteosarcoma cell fate.2018
Author(s)
Toru Hirozane, Mari Masuda, Naoko Goto, Teppei Sugano, Naofumi Asano, Eisuke Kobayashi, Akira Kawai, Keisuke Horiuchi, Morio Matsumoto, Masaya Nakamura, Masaaki Sawa, Hideo Morioka, Tesshi Yamada.
Organizer
2018 CTOS Annual Meeting
Related Report
Int'l Joint Research
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