Molecular characterization of H. pylori-infected cells associated with the development of gastric cancer

• Project/Area Number: 16K08349
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Environmental and hygienic pharmacy
• Research Institution: Keio University
• Principal Investigator: Tsugawa Hitoshi 慶應義塾大学, 医学部(信濃町), 講師 (30468483)
• Project Period (FY): 2016-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥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)
• 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

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.

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。

Research Products

• [Journal Article] CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobacter pylori CagA-degraded autophagy (2019)
  • Author(s): Tsugawa H., Mori H., Matsuzaki J., Sato A., Saito Y., Imoto M., Suematsu M., Suzuki H.
  • Journal Title: Autophagy Volume: 15 Issue: 2 Pages: 242-258
  • DOI: 10.1080/15548627.2018.1515530
  • Peer Reviewed / Open Access
• [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
• [Journal Article] Inhibiting xCT Improves 5-Fluorouracil Resistance of Gastric Cancer Induced by CD44 Variant 9 Expression. (2018)
  • Author(s): Miyoshi S, Tsugawa H, Matsuzaki J, Hirata K, Mori H, Saya H, Kanai T, Suzuki H.
  • Journal Title: Anticancer Research Volume: 38 Issue: 11 Pages: 6163-6170
  • DOI: 10.21873/anticanres.12969
  • Peer Reviewed
• [Journal Article] Enteric Glial Dysfunction Evoked by Apolipoprotein E Deficiency Contributes to Delayed Gastric Emptying. (2017)
  • Author(s): Fukuhara S, Masaoka T, Nishimura S, Nakamura M, Matsuzaki J, Tsugawa H, Miyoshi S, Mori H, Kawase S, Shibata S, Okano H, Kanai T, Suzuki H.
  • Journal Title: Dig Dis Sci. Volume: 62 Issue: 12 Pages: 3359-3369
  • DOI: 10.1007/s10620-017-4820-7
  • Peer Reviewed / Open Access
• [Journal Article] Sigma-2 receptor and progesterone receptor membrane component 1 (PGRMC1) are two different proteins: Proofs by fluorescent labeling and binding of sigma-2 receptor ligands to PGRMC1. (2016)
  • Author(s): Pati ML, Groza D, Riganti C, Kopecka J, Niso M, Berardi F, Hager S, Heffeter P, Hirai M, Tsugawa H, Kabe Y, Suematsu M, Abate C.
  • Journal Title: Pharmacological Research Volume: 117 Pages: 67-71
  • DOI: 10.1016/j.phrs.2016.12.023
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Efficacy of 10-day and 14-day triple therapy as a third-line and fourth-line regimen for Helicobacter pylori eradication: a pilot study. (2015)
  • Author(s): Mori, H., Suzuki, H.*, Matsuzaki, J., Tsugawa, H., Fukuhara, S., Miyoshi, S., Hirata, K., Seino, T., Matsushita, M., Nishizawa, T., Masaoka, T., Kanai, T.
  • Journal Title: United European Gastroenterology Journal Volume: - Issue: 3 Pages: 380-387
  • DOI: 10.1177/2050640615618043
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Efficacy of 10-day Sitafloxacin-containing third-line rescue therapies for Helicobacter pylori strains containing the gyrA mutation (2015)
  • Author(s): Mori H., Suzuki H., Matsuzaki J., Tsugawa H., Fukuhara S., Miyoshi S., Hirata K., Seino T., Matsushita M., Masaoka T., Kanai T.
  • Journal Title: Helicobacter Volume: 27 Issue: 4 Pages: 286-94
  • DOI: 10.1111/hel.12286
  • Peer Reviewed / Open Access
• [Presentation] Overexpression of CAPZA1, a novel negative regulator of autophagy, develops CD44v9-expressing cancer stem-like cells in Helicobacter pylori-infected gastric mucosa (2018)
  • Author(s): Tsugawa H, Matsuzaki J, Kato C, Mori H, Suematsu M, Suzuki H.
  • Organizer: XXXIst International Workshop on Helicobacter & Microbiota in Inflammation & Cancer
  • Int'l Joint Research
• [Presentation] Mechanisms of CD44v9-positive cancer stem cell development in H. pylori-infected gastric mucosa (2018)
  • Author(s): Tsugawa H
  • Organizer: The 17th Awaji International Forum on Infection and Immunity
  • Int'l Joint Research / Invited
• [Presentation] Association between oxidative stress and gastric carcinogenesis in H. pylori-infected patients (2018)
  • Author(s): Tsugawa H, Kato C, Mori H, Suematsu M, Suzuki H
  • Organizer: Summer School on Stress 2018
  • Int'l Joint Research / Invited
• [Presentation] Expression of CAPZA1, a negative regulator of CagA-degrading autophagy, is enhanced by oxidative stress-induced histone acetylation in Helicobacter pylori-infected gastric mucosa: A possible risk for gastric carcinogenesis (2018)
  • Author(s): Kato C, Tsugawa H, Saito Y, Suzuki H.
  • Organizer: Digestive Disease Week 2018
  • Int'l Joint Research
• [Presentation] Host-cell response against Helicobacter pylori-derived CagA oncoprotein (2018)
  • Author(s): Tsugawa H
  • Organizer: 第91回日本細菌学会総会(JKISM workshop)
  • Int'l Joint Research / Invited
• [Presentation] 宿主細胞内へ装填されたピロリ菌がん蛋白質CagAの安定性を規定する宿主細胞分子とその制御 (2018)
  • Author(s): 津川仁、加藤智尋、森英毅、松崎潤太郎、佐藤聡、斉藤義正、末松誠、 鈴木秀和
  • Organizer: 第65回トキシンシンポジウム
• [Presentation] 常在細菌の代謝産物butyrateはH. pylori感染胃粘膜において発がんリスクを増強する (2018)
  • Author(s): 津川仁、加藤智尋、斎藤義正、杉浦悠毅、松井英則、加部泰明、末松誠、鈴木秀和
  • Organizer: 第24回日本ヘリコバクター学会
• [Presentation] Host-cell response against Helicobacter pyloriderived CagA oncoprotein (2018)
  • Author(s): 津川仁
  • Organizer: 第91回日本細菌学会総会 日韓国際微生物シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] ピロリ菌感染による胃発がんリスクを高める宿主細胞特性 (2017)
  • Author(s): 津川仁
  • Organizer: 第90回日本細菌学会総会
  • Place of Presentation: 仙台国際センター
  • Year and Date: 2017-03-19
  • Invited
• [Presentation] 胃発がんリスク亢進に関わるCapZA1発現誘導機構 (2017)
  • Author(s): 加藤智尋、津川仁、斉藤義正、佐谷秀行、末松誠、鈴木秀和
  • Organizer: 第23回日本ヘリコバクター学会
• [Book] Autophagy. Helicoabcter pylori (2016)
  • Author(s): Tsugawa H., Suzuki H.
  • Total Pages: 5
  • Publisher: Springer