| Project/Area Number |
16K08349
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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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| Research Field |
Environmental and hygienic pharmacy
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| Research Institution | Keio University |
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Principal Investigator |
Tsugawa Hitoshi 慶應義塾大学, 医学部(信濃町), 講師 (30468483)
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| Project Period (FY) |
2016-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000)
Fiscal Year 2018: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | 癌幹細胞 / オートファジー / 胃癌 / ピロリ菌 / CAPZA1 / CD44 / 酸化ストレス / 胃がん / 病原細菌 / 細菌感染症 / がん幹細胞 / がんタンパク質 / CagA / VacA |
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| Outline of Final Research Achievements |
Helicobacter pylori-derived CagA plays a role as an oncogenic driver in gastric epithelial cells. However, upon delivery into gastric epithelial cells, CagA is usually degraded by autophagy. We report that enhancement of lysosome associated membrane protein 1 (LAMP1) expression is necessary for autophagolysosome formation. In contrast, CAPZA1 inhibits the LAMP1 expression in the nuclei. Thus, in CAPZA1-overexpressing gastric epithelial cells infected with H. pylori, autophagolysosome formation is inhibited and CagA escapes autophagic degradation. These findings identify CAPZA1 as a novel negative regulator of autophaglysosome formation and suggest that deregulation of CAPZA1 expression leads to increased risk of gastric carcinogenesis. Our findings demonstrate that regulation of autophagy by CAPZA1 could be a central mechanisms to account for the effects of CagA on gastric carcinogenesis, and represent new insight for understanding and manipulating the development of gastric cancer.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究ではオートファジー制御分子としてCAPZA1を同定し、CAPZA1の新規機能を明示した。今後の研究展開により、これまで隠されていたCAPZA1の本性が次々と明らかにされると期待できる。H. pylori感染者の中でも、胃癌発症者は4％であり、また、除菌後でも胃癌を発症する患者が存在する。これらの患者がなぜ胃癌発症者として選択されるのか明らかではなかった。本研究成果は、H. pylori感染者の中でもCAPZA1発現レベルの高い患者ほど胃発癌リスクが高まる事を示唆しており、今後、より制度の高い胃発癌リスク検診の開発に向けた応用研究が期待される。
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