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An epigenetic interplay between p53 deficiency and TGF-beta signalling initiates tumorigenesis

Research Project

Project/Area Number 22K17019
Research Category

Grant-in-Aid for Early-Career Scientists

Allocation TypeMulti-year Fund
Review Section Basic Section 57020:Oral pathobiological science-related
Research InstitutionKumamoto University

Principal Investigator

Date Yuki  熊本大学, 発生医学研究所, 特別研究員(PD) (70914240)

Project Period (FY) 2022-04-01 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2023: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Fiscal Year 2022: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
Keywordsp53 / Myc / TGFβ / 骨肉腫
Outline of Research at the Start

p53破綻とMyc過剰発現は、発がん性の代表的なゲノム・エピゲノム異常である。私たちは、p53破綻性の骨肉腫モデルマウスを用いて、Runx転写因子がMycの発現を過剰に誘導することを明らかにしてきた。しかし、p53破綻下の微小環境において、どの液性因子がどういう機序でMycを過剰に誘導するのか、その詳細はわかっていなかった。
本研究では、骨肉腫発症を助長する液性因子として、炎症関連サイトカインTGFβに着目し、骨肉腫発症におけるTGFβの発がん促進機序を明らかにする。

Outline of Final Research Achievements

Genomic mutations in the tumour suppressor gene p53 and the overexpression of the oncogene Myc are genomic and epigenomic abnormalities involved in the development and malignancy of many human cancers. In our previous studies, we have elucidated that the mechanism of osteosarcoma development, characterized by these two abnormalities, involves the excessive induction of Myc due to the disruption of p53. In our current study, we have clarified the molecular mechanism by which the TGF-beta signalling is enhanced in the tumour microenvironment under p53 disruption, leading to the overexpression of Myc. Specifically, in osteosarcoma cells, the Runx/Smad complex, which is activated downstream of the TGF-beta signalling, excessively induces Myc through the TGF-beta-responsive Myc enhancer dubbed ‘m340.’

Academic Significance and Societal Importance of the Research Achievements

本研究では、p53破綻下において、腫瘍微小環境由来のサイトカインであるTGFβが発がんを誘導する分子機序が明らかになった。TGFβは、発がん初期ではがん抑制的に働く一方で、発がん後期ではがん促進的に働くことが知られるが、その詳細な機序は分かっていなかった。この二層性の機序として、TGFβはp53が破綻した悪性腫瘍においては炎症促進因子に転化することが示された。また、同因子がMycエンハンサーを介して直接Mycを誘導し、発がんを引き起こすことがわかった。p53 破綻とTGFβシグナルの連動による発がん機序は、予後評価から治療に至るまで、がん種をこえた抗がん戦略となる可能性がある。

Report

(3 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Research-status Report
  • Research Products

    (3 results)

All 2023 2022

All Journal Article (2 results) (of which Peer Reviewed: 2 results,  Open Access: 1 results) Presentation (1 results) (of which Int'l Joint Research: 1 results)

  • [Journal Article] p53 Deficiency-Dependent Oncogenicity of Runx32023

    • Author(s)
      Ito Kosei、Otani Shohei、Date Yuki
    • Journal Title

      Cells

      Volume: 12 Issue: 8 Pages: 1122-1122

    • DOI

      10.3390/cells12081122

    • Related Report
      2023 Annual Research Report 2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] C/ebpα represses the oncogenic Runx3?Myc axis in p53-deficient osteosarcoma development2023

    • Author(s)
      Omori Keisuke、Otani Shohei、Date Yuki、Ueno Tomoya、Ito Tomoko、Umeda Masahiro、Ito Kosei
    • Journal Title

      Oncogene

      Volume: 42 Issue: 33 Pages: 2485-2494

    • DOI

      10.1038/s41388-023-02761-z

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Presentation] p53 deficiency causes Myc dysregulation through a novel TGFβ-facilitated promoter switching mechanism to instigate osteosarcoma development2022

    • Author(s)
      Yuki Date, Tomoya Ueno, and Kosei Ito
    • Organizer
      American Association for Cancer Research Annual Meeting
    • Related Report
      2022 Research-status Report
    • Int'l Joint Research

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Published: 2022-04-19   Modified: 2025-01-30  

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