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Hit-and-Run gastric carcinogenesis caused by H. pylori-mediated BRCA1 inactivation

Research Project

Project/Area Number 21H04804
Research Category

Grant-in-Aid for Scientific Research (A)

Allocation TypeSingle-year Grants
Section一般
Review Section Medium-sized Section 50:Oncology and related fields
Research InstitutionMicrobial Chemistry Research Foundation (2022-2023)
The University of Tokyo (2021)

Principal Investigator

Hatakeyama Masanori  公益財団法人微生物化学研究会, 微生物化学研究所, 部長 (40189551)

Project Period (FY) 2021-04-05 – 2024-03-31
Project Status Completed (Fiscal Year 2023)
Budget Amount *help
¥42,120,000 (Direct Cost: ¥32,400,000、Indirect Cost: ¥9,720,000)
Fiscal Year 2023: ¥13,130,000 (Direct Cost: ¥10,100,000、Indirect Cost: ¥3,030,000)
Fiscal Year 2022: ¥13,130,000 (Direct Cost: ¥10,100,000、Indirect Cost: ¥3,030,000)
Fiscal Year 2021: ¥15,860,000 (Direct Cost: ¥12,200,000、Indirect Cost: ¥3,660,000)
Keywords胃がん / ピロリ菌 CagA / BRCA1 / BRCAness / 相同組換え / DNA複製フォーク / ゲノム不安定性 / ヘリコバクター・ピロリ / CagA / ピロリ菌CagA / PAR1ファミリーキナーゼ / ヘリコバクター・ピロリ菌 / ゲノム変異シグネチャー
Outline of Research at the Start

胃がんは細菌が発がんの直接原因となることが証明された唯一のヒトがんであり、その発症には胃上皮細胞内に注入されたヘリコバクター・ピロリ菌がんタンパク質CagAによる宿主細胞内シグナルの撹乱が重要な役割を担う。さらに我々は最近、宿主細胞内に侵入したCagAが遺伝性乳がん/卵巣がん抑制遺伝子産物として知られるBRCA1の機能を間欠的に抑制しBRCAnessと呼ばれる特殊なゲノム不安定性を惹起することを見出した。そこで本研究では、CagAによるBRCAnessが引き起こす宿主遺伝子変異のレパートリー解明を通し、胃発がん過程をピロリ菌感染から発症までの時間軸に沿ったゲノム変異蓄積を通して明らかにする。

Outline of Final Research Achievements

The Helicobacter pylori CagA oncoprotein plays a vital role in the development of gastric cancer. Upon delivery into gastric epithelial cells via the bacterial micro-syringe, termed the type IV secretion system, CagA physically interacts with the serine/threonine kinase PAR1b and inactivates kinase activity. This study found that PAR1b promotes cytoplasmic-to-nuclear translocalization of the breast and ovarian cancer susceptibility gene product BRCA1 via phosphorylation on Ser-616. Upon injection into the host cells, however, CagA inhibits the nuclear delivery of cytoplasmic BRCA1 by turning off PAR1b-mediated BRCA1 phosphorylation, thereby depleting nuclear BRCA1, which elicits genomic instability similar to that induced by BRCA1 gene mutation. The risk of developing gastric cancer in individuals carrying a pathogenic BRCA1 variant (such as BRCA1, BRCA2, or PALB2) is robustly increased in the presence of H. pylori infection.

Academic Significance and Societal Importance of the Research Achievements

本研究から、ピロリ菌感染を基盤とする胃がんの発症と遺伝性乳がん・卵巣がん (HBOC) 発症との間に共通の分子機構が働いているというこれまで全く予想されてこなかった結論が導かれた、BRCA1に代表されるDNA相同組換え遺伝子の病的バリアント保有者は数百人に一人の頻度で存在する。これら病的バリアントの保有のみでは胃発がんリスクは微増にとどまるが、病的バリアント保有者がピロリ菌感染を受けている場合、胃発がんリスクは飛躍的に増加する。ピロリ菌感染者におけるBRCA関連遺伝子病的バリアントのスクリーニングは、胃がん高リスク群絞り込みの重要な手段になると考えられる。

Report

(5 results)
  • 2023 Annual Research Report   Final Research Report ( PDF )
  • 2022 Annual Research Report
  • 2021 Comments on the Screening Results   Annual Research Report
  • Research Products

    (52 results)

All 2024 2023 2022 2021 Other

All Journal Article (16 results) (of which Int'l Joint Research: 8 results,  Peer Reviewed: 14 results,  Open Access: 10 results) Presentation (31 results) (of which Int'l Joint Research: 16 results,  Invited: 20 results) Book (1 results) Remarks (4 results)

  • [Journal Article] Impaired glycosylation of gastric mucins drives gastric tumorigenesis and serves as a novel therapeutic target.2024

    • Author(s)
      Arai Junya、Hayakawa Yoku、Tateno Hiroaki、Murakami Keita、Hayashi Takeru、Hata Masahiro、Matsushita Yuki、Kinoshita Hiroto、Abe Sohei、Kurokawa Ken、Oya Yukiko、Tsuboi Mayo、Ihara Sozaburo、Niikura Ryota、et al.
    • Journal Title

      Gastroenterology

      Volume: . Issue: 3 Pages: 505-521.e19

    • DOI

      10.1053/j.gastro.2024.03.037

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Impact of the Helicobacter pylori Oncoprotein CagA in Gastric Carcinogenesis2023

    • Author(s)
      Hatakeyama Masanori
    • Journal Title

      Current Topics in Microbiology and Immunology

      Volume: 444 Pages: 239-257

    • DOI

      10.1007/978-3-031-47331-9_9

    • ISBN
      9783031473302, 9783031473319
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Exploring Allosteric Inhibitors of Protein Tyrosine Phosphatases Through High-Throughput Screening2023

    • Author(s)
      Hayashi Takeru、Hatakeyama Masanori
    • Journal Title

      Methods in Molecular Biology

      Volume: 2691 Pages: 235-245

    • DOI

      10.1007/978-1-0716-3331-1_18

    • ISBN
      9781071633304, 9781071633311
    • Related Report
      2023 Annual Research Report
    • Peer Reviewed
  • [Journal Article] Coevolution of the ileum with Brk/Ptk6 family kinases confers robustness to ileal homeostasis2023

    • Author(s)
      Ippei Kikuchi, Yusuke Iwashita, Atsushi Takahshi-Kanemitsu, Michinori Koebis, Atsu Aiba, Masanori Hatakeyama
    • Journal Title

      Biochemical and Biophysical Research Communications

      Volume: 676 Pages: 190-197

    • DOI

      10.1016/j.bbrc.2023.07.051

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] The Helicobacter pylori CagA oncoprotein disrupts Wnt/PCP signaling and promotes hyperproliferation of pyloric gland base cells2023

    • Author(s)
      Takahashi-Kanemitsu Atsushi、Lu Mengxue、Knight Christopher Takaya、Yamamoto Takayoshi、Hayashi Takuo、Mii Yusuke、Ooki Takuya、Kikuchi Ippei、Kikuchi Akira、Barker Nick、Susaki Etsuo A.、Taira Masanori、Hatakeyama Masanori
    • Journal Title

      Science Signaling

      Volume: 16 Issue: 794

    • DOI

      10.1126/scisignal.abp9020

    • Related Report
      2023 Annual Research Report
    • Peer Reviewed / Int'l Joint Research
  • [Journal Article] Diet-mediated constitutive induction of novel IL4+ ILC2 cells maintains intestinal homeostasis in mice2023

    • Author(s)
      Cui Wanlin, Nagano Yuji, Hatakeyama Masanori, Honda Kenya , et al.
    • Journal Title

      Journal of Experimental Medicine

      Volume: - Issue: 8

    • DOI

      10.1084/jem.20221773

    • Related Report
      2023 Annual Research Report 2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Non-H. pylori intragastric microbiome modulates procarcinogenic responses and predicts gastric cancer risk2023

    • Author(s)
      Niikura Ryota, Hayakawa Yoku, Hatakeyama Masanori, Fujihiro Mitsutoshi, et al.
    • Journal Title

      Gastro Hep Advances

      Volume: - Issue: 5 Pages: 684-700

    • DOI

      10.1016/j.gastha.2023.03.010

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Helicobacter pylori, homologous-recombination genes, and gastric cancer2023

    • Author(s)
      Usui Yoshiaki, Taniyama Yukari, Hatakeyama Masanori, Matsuo Keitaro, Momozawa Yukihide, etal.
    • Journal Title

      The New England Journal of Medicine

      Volume: 388 Issue: 13 Pages: 1181-1190

    • DOI

      10.1056/nejmoa2211807

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Kinase Activity of PAR1b, Which Mediates Nuclear Translocation of the BRCA1 Tumor Suppressor, Is Potentiated by Nucleic Acid-Mediated PAR1b Multimerization2022

    • Author(s)
      Hiroko Nishikawa, Priscillia Christiany, Takeru Hayashi, Hisashi Iizasa, Hironori Yoshiyama, Masanori Hatakeyama
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 12 Pages: 6634-6634

    • DOI

      10.3390/ijms23126634

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Transgenically expressed Helicobacter pylori CagA in vascular endothelial cells accelerates arteriosclerosis in mice.2022

    • Author(s)
      Tahmina K, Hikawa N, Takahashi-Kanemitsu A, Knight CT, Sato K, Itoh F, Hatakeyama M.
    • Journal Title

      Biochem Biophys Res Commun.

      Volume: 618 Pages: 79-85

    • DOI

      10.1016/j.bbrc.2022.06.010

    • Related Report
      2022 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Helicobacter pylori‐induced DNA double‐stranded break in the development of gastric cancer2022

    • Author(s)
      Murata‐Kamiya Naoko、Hatakeyama Masanori
    • Journal Title

      Cancer Science

      Volume: 113 Issue: 6 Pages: 1909-1918

    • DOI

      10.1111/cas.15357

    • Related Report
      2022 Annual Research Report 2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] ピロリ菌 CagAがんタンパク質による BRCAness誘導と Hit-and-Run型胃発がん2022

    • Author(s)
      畠山 昌則
    • Journal Title

      日本臨床((増刊号「臨床胃癌学ー基礎・臨床の最新動向」)

      Volume: 80 Pages: 62-68

    • Related Report
      2022 Annual Research Report
  • [Journal Article] ピロリ菌 CagAによるBRCA1抑制と Hit-and-Run型胃発がん機構2022

    • Author(s)
      畠山 昌則
    • Journal Title

      感染・炎症・免疫

      Volume: 52 Pages: 42-45

    • Related Report
      2022 Annual Research Report
  • [Journal Article] The H. pylori CagA Oncoprotein Induces DNA Double Strand Breaks through Fanconi Anemia Pathway Downregulation and Replication Fork Collapse2022

    • Author(s)
      Kolinjivadi Arun Mouli、Sankar Haresh、Choudhary Ramveer、Tay Lavina Sierra、Tan Tuan Zea、Murata-Kamiya Naoko、Voon Dominic Chih-Cheng、Kappei Dennis、Hatakeyama Masanori、Krishnan Vaidehi、Ito Yoshiaki
    • Journal Title

      International Journal of Molecular Sciences

      Volume: 23 Issue: 3 Pages: 1661-1661

    • DOI

      10.3390/ijms23031661

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Journal Article] Mouse gastric epithelial cells resist CagA delivery by the Helicobacter pylori Type IV secretion system2022

    • Author(s)
      Shrestha R, Murata-Kamiya N, Imai S, Yamamoto M, Tsukamoto T, Nomura S, Hatakeyama M
    • Journal Title

      International Journal of Molecular Science

      Volume: 23 Issue: 5 Pages: 2492-2492

    • DOI

      10.3390/ijms23052492

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access
  • [Journal Article] Helicobacter pylori CagA elicits BRCAness to induce genome instability that may underlie bacterial gastric carcinogenesis2021

    • Author(s)
      S Imai, T Ooki, N Murata-Kamiya, D Komura, K Tahmina, W Wu, Atsushi Takahashi-Kanemitsu, C T Knight, A Kunita, N Suzuki, A Del Valle, M Tsuboi, M Hata, Y Hayakawa, N Ohnishi, K Ueda, M Fukayama, T Ushiku, S Ishikawa, M Hatakeyama
    • Journal Title

      Cell Host & Microbe

      Volume: 29 Issue: 6 Pages: 1-18

    • DOI

      10.1016/j.chom.2021.04.006

    • Related Report
      2021 Annual Research Report
    • Peer Reviewed / Open Access / Int'l Joint Research
  • [Presentation] ヘリコバクターピロリのがんタンパク質CagAによる平面内細胞極性シグナルの脱制御を介した胃発がん促進機序2024

    • Author(s)
      金光 昌史、畠山 昌則、洲﨑 悦生
    • Organizer
      先端モデル動物支援プラットフォームAdAMS成果発表会
    • Related Report
      2023 Annual Research Report
  • [Presentation] The Helicobacter pylori CagA oncoprotein induces BRCAness-associated genome instability2024

    • Author(s)
      Hatakeyama Masanori
    • Organizer
      The 5th Japan-Taiwan Bilateral Conference on Protein Phosphatase
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ヘリコバクター・ピロリCagA, BRCAness, and genome instability2023

    • Author(s)
      畠山 昌則
    • Organizer
      第29回日本ヘリコバクター学会学術総会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Helicobacter pylori CagA perturbs non-canonical Wnt/planar cell polarity (Wnt/PCP) signaling, which mediates lineage specification of epithelial stem cells2023

    • Author(s)
      Hatakeyama Masanori, Takahashi-Kanemitsu Atsushi, Mengxue Lu
    • Organizer
      The 36th European Helicobacter and Microbiota Study Group (EHMSG) Annual Meeting
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ピロリ菌がんタンパク質CagAによる BRCAness誘導と胃発がん2023

    • Author(s)
      畠山 昌則
    • Organizer
      愛媛大学先端医療創生センター (TRC) 学術講演会 2023
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] Inhibition of the BRCA1 tumor suppressorby the Helicobacter pylori oncoprotein CagA2023

    • Author(s)
      Hatakeyama Masanori
    • Organizer
      Kanazawa University, Cancer Research Institute seminar
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] 膵癌細胞で高発現するがん代謝遺伝子による腫瘍微小環境適応機構の解明2023

    • Author(s)
      小野寺 威文、坂本 修一、川田 学、百瀬 功、畠山 昌則
    • Organizer
      第82回日本癌学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] MT-MMPの活性化を介して人小細胞はいがん細胞株 DM5273の浸潤及び転移形成を促進するクローディン2023

    • Author(s)
      坂本 修一、滝野 隆久、川田 学、畠山 昌則
    • Organizer
      第82回日本癌学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 冬虫夏草類培養液を用いた抗がん剤 in vivo スクリーニング系の構築2023

    • Author(s)
      大石 智一、安達 勇光、大庭 俊一、井上 裕幸、原川 晃子、橋本 奈々、吉田 潤二郎、立田 大輔、澤 竜一、川田 学、畠山 昌則
    • Organizer
      第82回日本癌学会学術総会
    • Related Report
      2023 Annual Research Report
  • [Presentation] 胃がん発症におけるピロリ菌 CagA依存的 BRCAness誘導の役割2023

    • Author(s)
      畠山 昌則
    • Organizer
      令和5年度「感染がん」全国共同研究拠点シンポジウム
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] The role of BRCA1 tumor suppressor in Helicobacter pylori-mediated gastric carcinogenesis2023

    • Author(s)
      Hatakeyama Masanori
    • Organizer
      The 51st International Symposium of the Princes Takamatsu Cancer Research Foundation
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] H. pylori CagA, BRCAness, and Gastric Cancer2023

    • Author(s)
      Hatakeyama Masanori
    • Organizer
      Helicobacter pylori Genomis, Signaling and Carcinogenesis (HGSC) Conference 2023
    • Related Report
      2023 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ピロリ菌CagAによるBRCA1の機能抑制とBRCAnessの誘導2023

    • Author(s)
      畠山 昌則
    • Organizer
      第14回がんゲノム・エピゲノム数理統計解析研究会
    • Related Report
      2023 Annual Research Report
    • Invited
  • [Presentation] ヘリコバクターピロリのがんタンパク質CagAはWnt/PCPシグナルの撹乱を介して胃上皮細胞の過増殖を促進する2023

    • Author(s)
      金光 昌史、盧 夢雪、畠山 昌則
    • Organizer
      第46回 日本分子生物学会年会
    • Related Report
      2023 Annual Research Report
  • [Presentation] BRCAness-associated genome instability induced by the Helicobacter pylori CagA oncoprotein2023

    • Author(s)
      畠山 昌則
    • Organizer
      International Conference on Emerging Infectious Diseases in the Pacific Rim
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] ピロリ菌による BRCAnessの誘導と胃発がん2023

    • Author(s)
      畠山 昌則
    • Organizer
      藤田医科大学がん医療研究センター・第12回がん医療研究セミナー
    • Related Report
      2022 Annual Research Report
    • Invited
  • [Presentation] Induction of transient BRCAness by the Helicobacter pylori CagA oncoprotein2022

    • Author(s)
      畠山 昌則
    • Organizer
      EMBO Symposium Microbial Infections and human cancer
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Induction of BRCAness and genomic instability by Helicobacter pylori CagA2022

    • Author(s)
      畠山 昌則
    • Organizer
      American Association for cancer Research Annual Meeting (AACR2022)
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Induction of BRCAness by the Helicobacter pylori CagA oncoprotein2022

    • Author(s)
      畠山 昌則
    • Organizer
      Franco-Japanese immuno-oncology webinar series
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Induction of Genome Instability by the Helicobacter pylori CagA Oncoprotein2022

    • Author(s)
      畠山 昌則
    • Organizer
      13th Annual Scientific Meeting of Singapore Gastric Cancer Consortium
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Carcinogenesis of CagA+ Helicobacter pylori in Gastric Cancer2022

    • Author(s)
      畠山 昌則
    • Organizer
      The Korea Gastric Cancer Week 2022 (KINGCA 2022)
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] H. pylori infection, BRCAness, and gastric cancer2022

    • Author(s)
      畠山 昌則
    • Organizer
      The 12th AACR-JCA Joint Conference on Breakthroughs in Cancer Research
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] Mouse gastric epithelial cells resist CagA delivery by cagA-positive Helicobacter pylori2022

    • Author(s)
      紙谷 尚子、畠山 昌則
    • Organizer
      第81回日本癌学会学術総会
    • Related Report
      2022 Annual Research Report
  • [Presentation] Screening and validation of a novel small chemical compound that inhibits pro-oncogenic signaling triggered by the Helicobacter pylori CagA oncoprotein2022

    • Author(s)
      林 剛瑠、千田 美紀、千田 俊哉、高谷 大輔、本間 輝樹、池田 亘、谷野 圭持、畠山 昌則
    • Organizer
      12th AACR-JCA Joint Conference, Breakthroughs in Cancer Research
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Ptk6 family kinases play a specific role in the maintenance of ileal mucosal homeostasis in the alimentary tract2022

    • Author(s)
      菊地 逸平、畠山 昌則
    • Organizer
      12th AACR-JCA Joint Conference, Breakthroughs in Cancer Research
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] The Helicobacter pylori CagA oncoprotein inhibits DNA damage-induced apoptosis through Hippo signal activation2022

    • Author(s)
      紙谷 尚子、大木 拓哉、畠山 昌則
    • Organizer
      12th AACR-JCA Joint Conference, Breakthroughs in Cancer Research
    • Related Report
      2022 Annual Research Report
    • Int'l Joint Research
  • [Presentation] ピロリ菌による胃発がん分子機構2021

    • Author(s)
      畠山 昌則
    • Organizer
      第45回鉄バイオサイエンス集会
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research
  • [Presentation] Helicobacter pylori CagA oncoprotein interacts with SHIP2 to ptomote its delivery into gastric epithelial cells2021

    • Author(s)
      畠山 昌則
    • Organizer
      The 14th International Conference on Protein Phosphatase
    • Related Report
      2021 Annual Research Report
    • Int'l Joint Research / Invited
  • [Presentation] 魅力ある英文論文を書くために2021

    • Author(s)
      畠山 昌則
    • Organizer
      第80回日本癌学会学術総会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ピロリ菌による Hit-and-Run型胃発がん機構2021

    • Author(s)
      畠山 昌則
    • Organizer
      微生物化学研究所セミナーシリーズ
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Presentation] ピロリ菌により胃がん発症機構2021

    • Author(s)
      畠山 昌則
    • Organizer
      第10回日本プロテインホスファターゼ研究会学術集会
    • Related Report
      2021 Annual Research Report
    • Invited
  • [Book] Research and Clinical Applications of Targeting Gastric Neoplasms2021

    • Author(s)
      Hatakeyama Masanori
    • Total Pages
      370
    • Publisher
      Elsevier
    • ISBN
      9780323855631
    • Related Report
      2021 Annual Research Report
  • [Remarks] 微生物化学研究所

    • URL

      https://www.bikaken.or.jp/laboratories/virology/summary.html

    • Related Report
      2023 Annual Research Report
  • [Remarks] 北海道大学遺伝子病制御研究所・感染癌研究センター

    • URL

      https://www.igm.hokudai.ac.jp/lab/index.html

    • Related Report
      2023 Annual Research Report
  • [Remarks] 微生物化学研究所 第3生物活性研究部

    • URL

      https://www.bikaken.or.jp/laboratories/virology/summary.html

    • Related Report
      2022 Annual Research Report
  • [Remarks]

    • URL

      http://www.microbiol.m.u-tokyo.ac.jp/

    • Related Report
      2021 Annual Research Report

URL: 

Published: 2021-04-28   Modified: 2025-01-30  

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