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Role of gastric microbiota on the development of gastric cacner stem-cells in H. pylori-infected gastric mucosa

Research Project

Project/Area Number 19K07068
Research Category

Grant-in-Aid for Scientific Research (C)

Allocation TypeMulti-year Fund
Section一般
Review Section Basic Section 47030:Pharmaceutical hygiene and biochemistry-related
Research InstitutionTokai University (2021)
Keio University (2019-2020)

Principal Investigator

Tsugawa Hitoshi  東海大学, 医学部, 講師 (30468483)

Project Period (FY) 2019-04-01 – 2022-03-31
Project Status Completed (Fiscal Year 2021)
Budget Amount *help
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Keywordsがん幹細胞 / ピロリ菌 / 胃内細菌叢 / 胃オルガノイド / 癌幹細胞 / CD44v9 / ステムセル / 胃がん / 胃内共生細菌 / 細菌叢 / 胃癌
Outline of Research at the Start

CD44v9陽性癌幹細胞は胃癌発症要因の責任細胞となるが、どの様に発生するか理解されていない。CAPZA1の過剰発現細胞はオートファジー不全となり、H. pyloriの癌蛋白質CagAを蓄積させる。CAPZA1発現はヒストンのアセチル化制御を受け、「消化管内短鎖脂肪酸は、CAPZA1発現を亢進させ、そこへのH. pylori感染により、CAPZA1過剰発現細胞はCD44v9陽性癌幹細胞へ脱分化される」と仮説できる。本研究課題では、H. pylori感染胃粘膜で消化管内細菌がSCFAsを介してCAPZA1発現を惹起しCD44v9陽性癌幹細胞の発生に寄与しているかを明らかにする。

Outline of Final Research Achievements

We identified two short-chain fatty acids (SCFAs)-producing bacteria that cause CAPZA1-overexpressing cells, which are precursors to CD44v9-positive cancer stem cells. It was clarified that CD44v9-positive cancer stem cells are produced by H. pylori infection in the presence of SCFAs produced by these bacteria. In H. pylori-infected mice given drinking water containig propionic acid or butyric acid, CD44v9-positive cells were generated through overexpression of CAPZA1 in gastric mucosal epithelial cells. Our results indicate that HDAC inhibitory activity of SCFAs deregulates CAPZA1 expression, and H. pylori infection under specific SCFAs-producing bacteria enhancces the development of CD44v9-positive cancer stem cells.

Academic Significance and Societal Importance of the Research Achievements

本研究成果により、がん幹細胞の発生過程に共生細菌が関与するというこれまでに類のない全く新しいがん幹細胞発生モデルを分子生物学的に提唱でき、学術的な発展が大いに期待できる。また、本研究成果を基盤に胃内共生細菌叢への介入による胃がんの発症・再発リスク評価系や胃発がん予防・治療法の開発も期待され、今日のがん予防・治療法に革新的な変化をもたらし、臨床医学的にも期待値の大きい基礎エビデンスの提唱が実現される。

Report

(4 results)
  • 2021 Annual Research Report   Final Research Report ( PDF )
  • 2020 Research-status Report
  • 2019 Research-status Report
  • Research Products

    (22 results)

All 2022 2021 2020 2019

All Journal Article (9 results) (of which Peer Reviewed: 5 results,  Open Access: 3 results) Presentation (13 results) (of which Int'l Joint Research: 1 results,  Invited: 4 results)

  • [Journal Article] 短鎖飽和脂肪酸:新しいガスメディエータによる免疫機能制御2022

    • Author(s)
      津川仁
    • Journal Title

      細胞

      Volume: 54 Pages: 8-11

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Glycyrrhizin derivatives suppress cancer chemoresistance by inhibiting progesterone receptor membrane component 12021

    • Author(s)
      Yasuaki Kabe, Ikko Koike, Tatsuya Yamamoto, Miwa Hirai, Ayaka Kanai, Ryogo Furuhata, Hitoshi Tsugawa, Erisa Harada, Kenji Sugase, Kazue Hanadate, Nobuji Yoshikawa, Hiroaki Hayashi, Masanori Noda, Susumu Uchiyama, Hiroki Yamazaki, Hirotoshi Tanaka, Takuya Kobayashi, Hiroshi Handa, Makoto Suematsu.
    • Journal Title

      Cancers (Basel)

      Volume: 13 Issue: 13 Pages: 3265-3265

    • DOI

      10.3390/cancers13133265

    • URL

      https://pure.teikyo.jp/en/publications/12bf5c55-ce9a-4604-a017-5925a61f3fc1

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] 胃がんの発症を制御する胃内の細菌2021

    • Author(s)
      津川仁
    • Journal Title

      日本がん予防学会News Letter

      Volume: 107 Pages: 4-4

    • Related Report
      2021 Annual Research Report
  • [Journal Article] H. pylori病原性, 病態発生の最新知見.2021

    • Author(s)
      津川仁
    • Journal Title

      日本ヘリコバクター学会誌

      Volume: 23 Pages: 17-17

    • Related Report
      2021 Annual Research Report
  • [Journal Article] Short-chain fatty acids bind to apoptosis-associated speck-like protein to activate inflammasome complex to prevent Salmonella infection2020

    • Author(s)
      Tsugawa Hitoshi、Kabe Yasuaki、Kanai Ayaka、Sugiura Yuki、Hida Shigeaki、Taniguchi Shun’ichiro、Takahashi Toshio、Matsui Hidenori、Yasukawa Zenta、Itou Hiroyuki、Takubo Keiyo、Suzuki Hidekazu、Honda Kenya、Handa Hiroshi、Suematsu Makoto
    • Journal Title

      PLOS Biology

      Volume: 18 Issue: 9 Pages: 3000813-3000813

    • DOI

      10.1371/journal.pbio.3000813

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Progesterone receptor membrane associated component 1 enhances obesity progression in mice by facilitating lipid accumulation in adipocytes2020

    • Author(s)
      Furuhata Ryogo、Kabe Yasuaki、Kanai Ayaka、Sugiura Yuki、Tsugawa Hitoshi、Sugiyama Eiji、Hirai Miwa、Yamamoto Takehiro、Koike Ikko、Yoshikawa Noritada、Tanaka Hirotoshi、Koseki Masahiro、Nakae Jun、Matsumoto Morio、Nakamura Masaya、Suematsu Makoto
    • Journal Title

      Communications Biology

      Volume: 3 Issue: 1 Pages: 479-479

    • DOI

      10.1038/s42003-020-01202-x

    • Related Report
      2020 Research-status Report
    • Peer Reviewed / Open Access
  • [Journal Article] Precision Medicine Approaches to Prevent Gastric Cancer2020

    • Author(s)
      Matsuzaki Juntaro、Tsugawa Hitoshi、Suzuki Hidekazu
    • Journal Title

      Gut and Liver

      Volume: Epub Issue: 1 Pages: 3-12

    • DOI

      10.5009/gnl19257

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] Cancer Stem-Cell Marker CD44v9-Positive Cells Arise From Helicobacter pylori?Infected CAPZA1-Overexpressing Cells2019

    • Author(s)
      Tsugawa Hitoshi、Kato Chihiro、Mori Hideki、Matsuzaki Juntaro、Kameyama Kaori、Saya Hideyuki、Hatakeyama Masanori、Suematsu Makoto、Suzuki Hidekazu
    • Journal Title

      Cellular and Molecular Gastroenterology and Hepatology

      Volume: 8 Issue: 3 Pages: 319-334

    • DOI

      10.1016/j.jcmgh.2019.05.008

    • Related Report
      2019 Research-status Report
    • Peer Reviewed
  • [Journal Article] マイクロバイオータとH. pylori感染2019

    • Author(s)
      津川仁
    • Journal Title

      日本ヘリコバクター学会誌

      Volume: 20 Pages: 112-117

    • Related Report
      2019 Research-status Report
  • [Presentation] 消化管内共生Pathobiont Klebsiella pneumoniaeの上皮細胞標的化の開始起点2022

    • Author(s)
      津川仁, 鈴木秀和
    • Organizer
      第95回日本細菌学会総会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 加齢に伴う腸管粘膜フロントラインバリアの脆弱化による消化管内共生Pathobiont Klebsiella pneumoniaeの病原性発揮点2022

    • Author(s)
      津川仁, 田中里佳, 上田孝, 鈴木秀和
    • Organizer
      第40回サイトプロテクション研究会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 発がん過程を加速させる消化管内共生pathobiontの悪巧み2022

    • Author(s)
      津川仁
    • Organizer
      日本薬学会142年会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] Role of gastric non-Helicobacter commensal bacteria in the development of CD44v9-positive cancer stem cells2021

    • Author(s)
      津川仁, 鈴木秀和
    • Organizer
      第80回日本癌学会
    • Related Report
      2021 Annual Research Report
  • [Presentation] CD44v9陽性胃癌幹細胞発生過程に対する胃内共生細菌とH. pyloriの協調2021

    • Author(s)
      津川仁
    • Organizer
      第27回日本ヘリコバクター学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 腸内細菌叢に含まれる潜在的病原細菌を制御する腸管粘膜バリア機構2021

    • Author(s)
      津川仁
    • Organizer
      第74回日本酸化ストレス学会学術集会
    • Related Report
      2021 Annual Research Report
  • [Presentation] 消化管内環境と相互作用する生体防御力に呼応する病原細菌の挙動2021

    • Author(s)
      津川仁
    • Organizer
      第94回日本細菌学会総会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] 胃オルガノイド由来単層上皮培養系を用いたCagA依存的CD44v9陽性癌幹細胞の発生メカニズムの解析2021

    • Author(s)
      津川仁、鈴木秀和
    • Organizer
      第26回日本ヘリコバクター学会
    • Related Report
      2020 Research-status Report
    • Invited
  • [Presentation] ピロリ菌と協調して胃癌発症に寄与する胃内共生細菌の探索とその役割2020

    • Author(s)
      津川仁, 末松誠, 鈴木秀和
    • Organizer
      第93回日本細菌学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] H. pylori感染によるCD44v9陽性胃がん幹細胞発生メカニズム2020

    • Author(s)
      津川仁、末松誠、鈴木秀和
    • Organizer
      第47回日本潰瘍学会・第21回日本神経消化器病学会
    • Related Report
      2019 Research-status Report
  • [Presentation] H. pylori感染によるCD44v9陽性胃がん幹細胞発生メカニズム2020

    • Author(s)
      津川仁
    • Organizer
      第47回日本潰瘍学会・第21回日本神経消化器病学会 「ランチョンセミナー講演」
    • Related Report
      2019 Research-status Report
    • Invited
  • [Presentation] Role of host innate immunity regulated by microbiota for protection against Salmonella infection2019

    • Author(s)
      津川仁、金井彩香、杉浦悠毅、鈴木秀和、末松誠、加部泰明
    • Organizer
      第92回日本細菌学会総会
    • Related Report
      2019 Research-status Report
  • [Presentation] Molecular characterization of the gastric commensal bacteria progressing gastric carcinogenesis in H. pylori-infected gastric mucosa2019

    • Author(s)
      Tsugawa H, Matsuzaki J, Mori H, Suematsu M, Suzuki H.
    • Organizer
      XXXII International Workshop on Helicobacter & Microbiota in Inflammation & Cancer
    • Related Report
      2019 Research-status Report
    • Int'l Joint Research

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Published: 2019-04-18   Modified: 2023-01-30  

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