Understanding of the mechanism of gastric carcinogenesis by the development of the system that visualizes dynamics of the planar cell polarity within gastric epithelial organoids
| Project/Area Number |
19K05945
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Review Section |
Basic Section 38060:Applied molecular and cellular biology-related
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| Research Institution | The University of Tokyo |
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Principal Investigator |
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000)
Fiscal Year 2021: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
Fiscal Year 2020: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2019: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
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| Keywords | Wntシグナル伝達系 / 平面内細胞極性 / ヘリコバクター・ピロリ / CagA / PAR1b / Hippoシグナル伝達系 / Want-PCPシグナル伝達経路 / BRCA1 / DNA傷害の相同組替え修復 / ゲノム不安定性の誘導 / Helicobacter pylori / 平面内細胞極性/PCP極性 / PAR1b/MARK2 / 頂底細胞極性/A-B細胞極性 / Wnt-PCPシグナル伝達 / CagAタンパク質 / ヘリコバクター・ピロリ（ピロリ菌） / 胃発がん |
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| Outline of Research at the Start |
私は今日までにピロリ菌由来発がんタンパク質CagAが①Wnt-PCP（Planar Cell Polarity：平面内細胞極性）シグナル伝達を撹乱すること；②PCP主要制御分子と細胞内で複合体を形成することを見出している。本研究では、哺乳動物胃上皮由来試料のPCP極性動態を可視化する解析系を新規に開発することで、胃上皮組織の恒常性維持にPCP極性制御が果たす役割を明らかにする。同時に、CagAが胃上皮細胞内でPCPシグナル／PCP極性の脱制御を引き起こす分子機序を明らかにし、PCP極性の破壊が胃がんやその他の胃粘膜病変の発症に促進的に寄与するか検討を行う。
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| Outline of Final Research Achievements |
I revealed that a bacterial oncoprotein CagA, which is injected into the gastric epithelial cells by Helicobacter pylori, has an activity to perturb the Wnt-Planar Cell Polarity (PCP) signaling pathway. The CagA-caused perturbation of Wnt-PCP signaling was due to the CagA-Protein X (a PCP core protein) complex formation via the N-terminal domain of the CagA protein. We identified BRCA1 as a novel substrate of PAR1b, a kinase responsible for apical-basal cell polarity. CagA inhibits the kinase activity of PAR1b therefore we found that CagA prevents the phosphorylation-dependent nuclear translocation of BRCA1, which is required for homologous recombination-driven repairing of DNA double strand breaks. The human YAP1 gene generates 8 isoforms through alternative splicing. We found that an alternative exon, the exon 6, plays a key role in the tumorigenic potential of the YAP protein in the subcutaneous of nude mice and then uncovered the molecular mechanism underlaying the phenomenon.
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| Academic Significance and Societal Importance of the Research Achievements |
頂端細胞極性に関わるPAR1bがゲノム安定性を制御することを示した。PAR1bはYAP1を介したHippoシグナルや平面内細胞極性の制御に重要である。本研究では、ピロリ菌のCagAによる「頂端/平面内細胞極性ーDNA傷害の修復ーHippoシグナル」の機能連関の撹乱を示した。病理学・疫学的な解析から、ピロリ菌／CagAは胃発がんに不可欠である。多段階発がん過程を経た胃のがん部にはピロリ菌は存在しないことから、CagAの注入が胃のがん化を開始する一方で、胃がん形成後にはCagAは不要であると考えられてきた（Hit and Run型の発がん）。本研究は世界に先駆けてこの機序を明らかにした。
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Report
(4 results)
Research Products
(10 results)
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[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
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Journal Title
Cell Host & Microbe
Volume: 29
Issue: 6
Pages: 1-18
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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