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Role of precancerous cells as components of the tumor microenvironment

Research Project

Project/Area Number 22K19450
Research Category

Grant-in-Aid for Challenging Research (Exploratory)

Allocation TypeMulti-year Fund
Review Section Medium-sized Section 50:Oncology and related fields
Research InstitutionTohoku University

Principal Investigator

Yamamoto Masayuki  東北大学, 東北メディカル・メガバンク機構, 教授 (50166823)

Co-Investigator(Kenkyū-buntansha) 鈴木 未来子  東北大学, 医学系研究科, 准教授 (80508309)
Project Period (FY) 2022-06-30 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥6,370,000 (Direct Cost: ¥4,900,000、Indirect Cost: ¥1,470,000)
Fiscal Year 2023: ¥2,990,000 (Direct Cost: ¥2,300,000、Indirect Cost: ¥690,000)
Fiscal Year 2022: ¥3,380,000 (Direct Cost: ¥2,600,000、Indirect Cost: ¥780,000)
Keywordsがん悪性化 / NRF2 / 前がん細胞 / 食道がん / EVI1 / 白血病
Outline of Research at the Start

腫瘍組織は、様々な細胞で構成されている。本研究は、がん微小環境を構成する一員であるにもかかわらず、今まで見過ごされてきた「前がん細胞」に焦点をあて、前がん細胞が、がん細胞に及ぼす役割を解析する。急性骨髄性白血病では、前がん細胞由来の巨核球が白血病幹細胞を支持する機能を検証する。食道扁平上皮がんでは、物理的に接している細胞同士の競合において、正常細胞とがん細胞とのバリアとして働く機能を検証する。

Outline of Final Research Achievements

Many cancer cells are formed by accumulating DNA mutations over a long period of time. During this process, various pre-cancerous cells are produced. Pre-cancerous cells have been regarded as merely an intermediate stage in the formation of cancer cells, and their other roles have not been considered. In this study, we focused on the KEAP1-NRF2 system, which is known to be involved in the malignant transformation of many cancers, and revealed that even in malignant tumors accompanied by NRF2 activation, tumors can be suppressed by activating NRF2 in surrounding normal cells. We also discovered that squamous epithelial cells with KEAP1 gene mutations disappear, whereas squamous epithelial cells with NRF2 gene mutations can survive for a long time.

Academic Significance and Societal Importance of the Research Achievements

本研究の成果は、前がん細胞からがん細胞の形成過程において、KEAP1-NRF2系の変異が重要な役割を担うことを明らかにした。この知見は、悪性度の高いNRF2活性化がんの治療法の開発に有益な情報を与えるものである。また、本研究では、NRF2が活性化したがんモデルマウスの作出にも成功した。今後、同モデルマウスの新規治療薬開発へ向けた応用が進むものと期待される。

Report

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

    (13 results)

All 2024 2023 2022 Other

All Int'l Joint Research (2 results) Journal Article (8 results) (of which Int'l Joint Research: 1 results,  Peer Reviewed: 8 results,  Open Access: 6 results) Presentation (2 results) Remarks (1 results)

  • [Int'l Joint Research] Fred Hutchinson Cancer Center(米国)

    • Related Report
      2023 Annual Research Report
  • [Int'l Joint Research] University of Dundee(英国)

    • Related Report
      2023 Annual Research Report
  • [Journal Article] Differential squamous cell fates elicited by NRF2 gain of function versus KEAP1 loss of function2024

    • Author(s)
      Takahashi Jun、Suzuki Takafumi、Sato Miu、Nitta Shuji、Yaguchi Nahoko、Muta Tatsuki、Tsuchida Kouhei、Suda Hiromi、Morita Masanobu、Hamada Shin、Masamune Atsushi、Takahashi Satoru、Kamei Takashi、Yamamoto Masayuki
    • Journal Title

      Cell Reports

      Volume: 43 Issue: 4 Pages: 114104-114104

    • DOI

      10.1016/j.celrep.2024.114104

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Whole blood transcriptome analysis for age- and gender-specific gene expression profiling in Japanese individuals2023

    • Author(s)
      Aoki YI, Taguchi K, Anzawa H, Kawashima J, Ishida N, Otuki A, Hasegawa A, Baird L, Suzuki T, Motoike IN, Ohneda K, Kumada K, Katsuoka F, Kinoshita K, Yamamoto M.
    • Journal Title

      J Biochem

      Volume: Online ahead of print. Issue: 6 Pages: 611-627

    • DOI

      10.1093/jb/mvae008

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Nrf2 alleviates spaceflight-induced immunosuppression and thrombotic microangiopathy in mice2023

    • Author(s)
      Shimizu Ritsuko、Hirano Ikuo、Hasegawa Atsushi、Suzuki Mikiko、Otsuki Akihito、Taguchi Keiko、Katsuoka Fumiki、Uruno Akira、Suzuki Norio、Yumoto Akane、Okada Risa、Shirakawa Masaki、Shiba Dai、Takahashi Satoru、Suzuki Takafumi、Yamamoto Masayuki
    • Journal Title

      Communications Biology

      Volume: 6 Issue: 1 Pages: 875-875

    • DOI

      10.1038/s42003-023-05251-w

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Effects of NRF2 polymorphisms on safety and efficacy of bardoxolone methyl: subanalysis of TSUBAKI study2023

    • Author(s)
      Ikejiri Kazuaki、Suzuki Takafumi、Muto Satsuki、Takama Hirotaka、Yamawaki Kengo、Miyazawa Tatsuya、Urakawa Itaru、Aoki Yuichi、Otsuki Akihito、Katsuoka Fumiki、Kinoshita Kengo、Nangaku Masaomi、Akizawa Tadao、Yamamoto Masayuki
    • Journal Title

      Clinical and Experimental Nephrology

      Volume: 28 Issue: 3 Pages: 225-234

    • DOI

      10.1007/s10157-023-02427-w

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Nrf2 activation improves experimental rheumatoid arthritis2023

    • Author(s)
      Zhang Anqi、Suzuki Takafumi、Adachi Saki、Yoshida Eiki、Sakaguchi Shimon、Yamamoto Masayuki
    • Journal Title

      Free Radical Biology and Medicine

      Volume: 207 Pages: 279-295

    • DOI

      10.1016/j.freeradbiomed.2023.07.016

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Selective Elimination of NRF2-Activated Cells by Competition With Neighboring Cells in the Esophageal Epithelium2023

    • Author(s)
      Hirose Wataru、Horiuchi Makoto、Li Donghan、Motoike Ikuko N.、Zhang Lin、Nishi Hafumi、Taniyama Yusuke、Kamei Takashi、Suzuki Mikiko、Kinoshita Kengo、Katsuoka Fumiki、Taguchi Keiko、Yamamoto Masayuki
    • Journal Title

      Cellular and Molecular Gastroenterology and Hepatology

      Volume: 15 Issue: 1 Pages: 153-178

    • DOI

      10.1016/j.jcmgh.2022.09.004

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The β-TrCP-Mediated Pathway Cooperates with the Keap1-Mediated Pathway in Nrf2 Degradation <i>In Vivo</i>2022

    • Author(s)
      Kuga Ayumi、Tsuchida Kouhei、Panda Harit、Horiuchi Makoto、Otsuki Akihito、Taguchi Keiko、Katsuoka Fumiki、Suzuki Mikiko、Yamamoto Masayuki
    • Journal Title

      Molecular and Cellular Biology

      Volume: 42 Issue: 7 Pages: 1-22

    • DOI

      10.1128/mcb.00563-21

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] The KEAP1-NRF2 system and esophageal cancer2022

    • Author(s)
      Hirose W, Oshikiri H, Taguchi K, Yamamoto M
    • Journal Title

      Cancers

      Volume: 14 Issue: 19 Pages: 4702-4702

    • DOI

      10.3390/cancers14194702

    • Related Report
      2022 Research-status Report
    • Peer Reviewed / Open Access
  • [Presentation] 食道上皮におけるNrf2活性化細胞の周囲細胞の代償的増殖2022

    • Author(s)
      廣瀬亘、田口恵子、山本雅之
    • Organizer
      日本生化学会東北支部第88回例会・シンポジウム
    • Related Report
      2022 Research-status Report
  • [Presentation] 細胞競合によるNRF2活性化細胞の排除機構2022

    • Author(s)
      廣瀬亘、堀内真、田口恵子、谷山祐亮、山本雅之、亀井尚
    • Organizer
      第76回日本食道学会学術集会
    • Related Report
      2022 Research-status Report
  • [Remarks] 東北大学 東北メディカル・メガバンク機構 分子医化学分野

    • URL

      http://www.dmbc.med.tohoku.ac.jp/official/index.html

    • Related Report
      2023 Annual Research Report

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Published: 2022-07-05   Modified: 2025-01-30  

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