Tsugawa, Hitoshi

写真a

Affiliation

School of Medicine, Department of Biochemistry (Shinanomachi)

Position

Senior Assistant Professor (Non-tenured)/Assistant Professor (Non-tenured)

E-mail Address

E-mail address

Academic Degrees 【 Display / hide

  • 博士(薬学), 東北薬科大学大学院 薬学研究科

Licenses and Qualifications 【 Display / hide

  • 薬剤師

 

Research Areas 【 Display / hide

  • General medical chemistry

  • Bacteriology (including mycology)

 

Books 【 Display / hide

  • H. pylori感染症を制御する病原因子と宿主細胞応答

    津川 仁, 鈴木秀和, 日本防菌防黴学会誌, 2018

  • H. pylori感染症と宿主免疫応答.

    津川 仁, 鈴木秀和, 臨床と微生物, 2015

  • Helicobacter pylori感染とオートファジー

    鈴木 秀和, 津川 仁, G.I.Reserch, 2015

  • H. pyloriがん蛋白質CagAのCD44v9発現がん幹細胞特異的蓄積メカニズムの発見-細胞内CagA安定性を規定する細胞表層LRP1のautophagy制御機構-

    津川 仁, 日本ヘリコバクター学会誌, 2014

  • ピロリ菌の感染戦略と胃がん発症に関わる宿主応答機構の解析

    津川 仁, 日本細菌学雑誌, 2014

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Papers 【 Display / hide

  • CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobacter pylori CagA-degraded autophagy

    Tsugawa H., Mori H., Matsuzaki J., Sato A., Saito Y., Imoto M., Suematsu M., Suzuki H.

    Autophagy (Autophagy)  15 ( 2 ) 242 - 258 2019.02

    ISSN  15548627

     View Summary

    © 2018, © 2018 Informa UK Limited, trading as Taylor & Francis Group. Helicobacter pylori-derived CagA, a type IV secretion system effector, plays a role as an oncogenic driver in gastric epithelial cells. However, upon delivery into gastric epithelial cells, CagA is usually degraded by macroautophagy/autophagy. Hence, the induction of autophagy in H. pylori-infected epithelial cells is an important host-protective ability against gastric carcinogenesis. However, the mechanisms by which autophagosome-lysosome fusion is regulated, are unknown. Here, we report that enhancement of LAMP1 (lysosomal associated membrane protein 1) expression is necessary for autolysosome formation. LAMP1 expression is induced by nuclear translocated LRP1 (LDL receptor related protein 1) intracellular domain (LRP1-ICD) binding to the proximal LAMP1 promoter region. Nuclear translocation of LRP1-ICD is enhanced by H. pylori infection. In contrast, CAPZA1 (capping actin protein of muscle Z-line alpha subunit 1) inhibits LAMP1 expression via binding to LRP1-ICD in the nuclei. The binding of CAPZA1 to LRP1-ICD prevents LRP1-ICD binding to the LAMP1 proximal promoter. Thus, in CAPZA1-overexpressing gastric epithelial cells infected with H. pylori, autolysosome formation is inhibited and CagA escapes autophagic degradation. These findings identify CAPZA1 as a novel negative regulator of autolysosome formation and suggest that deregulation of CAPZA1 expression leads to increased risk of gastric carcinogenesis. Abbreviations: CagA: cytotoxin-associated gene A; CAPZA1: capping actin protein of muscle Z-line alpha subunit 1; ChIP: chromatin immunoprecipitation; GTF2I: general transcription factor IIi; HDAC: histone deacetylase; LAMP1: lysosomal associated membrane protein 1; LRP1: LDL receptor related protein 1; LRP1-ICD: CagA intracellular domain; qPCR: quantitative polymerase chain reaction; VacA: vacuolating cytotoxin.

  • Neutrophil-activating Protein Polymorphism of Helicobacter pylori Determines the Host Risk of Dyspepsia

    Matsuzaki J., Tsugawa H., Kashiwazaki Y., Mori H., Yamamoto Y., Kameyama H., Masaoka T., Kanai T., Suzuki H.

    Cellular and Molecular Gastroenterology and Hepatology (Cellular and Molecular Gastroenterology and Hepatology)  8 ( 2 ) 295 - 297.e6 2019

  • Cancer Stem-Cell Marker CD44v9-Positive Cells Arise From Helicobacter pylori–Infected CAPZA1-Overexpressing Cells

    Tsugawa H., Kato C., Mori H., Matsuzaki J., Kameyama K., Saya H., Hatakeyama M., Suematsu M., Suzuki H.

    Cellular and Molecular Gastroenterology and Hepatology (Cellular and Molecular Gastroenterology and Hepatology)  8 ( 3 ) 319 - 334 2019

     View Summary

    © 2019 The Authors Background & Aims: CD44 variant 9 (CD44v9)-positive cancer stem-like cells strongly contribute to the development and recurrence of gastric cancer. However, the origin of CD44v9-positive cells is uncertain. Methods: CD44v9, β-catenin, and epithelial splicing regulatory protein 1 signals were assessed by real-time reverse-transcription polymerase chain reaction, immunoblot analysis, or immunofluorescence microscopy. Capping actin protein of muscle Z-line α subunit 1 (CAPZA1) expression was assessed by immunoblot analysis or immunohistochemical analysis of Mongolian gerbils' gastric mucosa or human biopsy specimens. Levels of oxidative stress were assessed by measuring malondialdehyde and protein carbonylation. Histone H3 acetylation levels in the CAPZA1 proximal promoter region were measured by using chromatin immunoprecipitation analysis with an antibody against the acetylated histone H3 in human gastric carcinoma cell line (AGS) cells. Results: CD44v9 is expressed in CAPZA1-overexpressing cells in human gastric cancer tissues. CAPZA1 overexpression enhanced expression of β-catenin, which is a transcription factor for CD44, and epithelial splicing regulatory protein 1, which increases alternative splicing of CD44 to generate CD44v9. CAPZA1-overexpressing cells after cytotoxin-associated gene A accumulation showed CD44v9 expression by inducing nuclear accumulation of β-catenin, concomitant with the enhancement of expression of Sal-like protein 4 and Krüppel-like factor 5, which encode reprogramming factors. Oxidative stress increased the CAPZA1 expression in AGS cells through the enhancement of histone H3 acetylation of CAPZA1 promoter. CAPZA1 expression was increased depending on oxidative stress in H pylori–infected gastric mucosa. Conclusions: CD44v9 expression is evoked from CAPZA1-overexpressing cells after accumulation of cytotoxin-associated gene A. Our findings provide important insights into the mechanisms underlying the development of CD44v9-positive cells.

  • Inhibiting xCT improves 5-fluorouracil resistance of gastric cancer induced by CD44 variant 9 expression

    Miyoshi S., Tsugawa H., Matsuzaki J., Hirata K., Mori H., Saya H., Kanai T., Suzuki H.

    Anticancer Research (Anticancer Research)  38 ( 11 ) 6163 - 6170 2018.11

    ISSN  02507005

     View Summary

    © 2018 International Institute of Anticancer Research.All right reserved. Background/Aim: Cancer stem cells (CSCs) play a critical role in resistance to chemotherapy. CD44 is a cell surface marker of CSCs. CD44 variant 9 (CD44v9) interacts with a cystine-glutamate antiporter (xCT) and is an unfavorable predictive factor in gastric cancer. We investigated the impact of CD44v9 expression on 5-fluorouracil (5-FU) resistance and the efficacy of the xCT inhibitor, sulfasalazine (SASP), in improving drug resistance. Materials and Methods: The human gastric cancer cell line MKN28 was transfected with pRc/CMV plasmids encoding human CD44 or CD44v9, which were used for in vitro and in vivo experiments. Results: CD44v9 expression results in 5-FU resistance by increasing intracellular glutathione and suppressing the drug-induced production of reactive oxygen species (ROS). SASP improved the drug sensitivity of CD44v9-expressing cells. Conclusion: Inhibition of xCT improved the clinical efficacy of chemotherapy against gastric cancer. CD44v9 expression can be a novel biomarker to predict resistance against 5-FU in gastric cancer.

  • CAPZA1 determines the risk of gastric carcinogenesis by inhibiting Helicobcater pylori CagA-degraded autophagy.

    Tsugawa H., Mori H., Matsuzaki J., Sato A., Saito Y., Imoto M., Suematsu M., Suzuki H.

    Autophagy Epub ahead of print 2018

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Papers, etc., Registered in KOARA 【 Display / hide

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Presentations 【 Display / hide

  • 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

    Tsugawa Hitoshi

    第65回トキシンシンポジウム, 2018, Oral Presentation(general)

  • Overexpression of CAPZA1, a novel negative regulator of autophagy, develops CD44v9-expressing cancer stem-like cells in Helicobacter pylori-infected gastric mucosa

    Tsugawa H., Matsuzaki J., Kato C., Mori H., Suematsu M., Suzuki H.

    XXXIst International Workshop on Helicobacter & Microbiota in Inflammation & Cancer, 2018, Poster (general)

  • Mechanisms of CD44v9-positive cancer stem cell development in H. pylori-infected gastric mucosa

    Tsugawa H.

    The 17th Awaji International Forum on Infection and Immunity, 2018, Oral Presentation(guest/special)

  • Association between oxidative stress and gastric carcinogenesis in H. pylori-infected patients

    Tsugawa H., Kato C., Mori H., Suematsu M., Suzuki H.

    Summer School on Stress 2018, 2018, Oral Presentation(guest/special)

  • 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

    Kato C., Tsugawa H., Saito Y., Suzuki H.

    Digestive Disease Week 2018, 2018, Oral Presentation(general)

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Research Projects of Competitive Funds, etc. 【 Display / hide

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

    2019.04
    -
    2022.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 津川 仁, Grant-in-Aid for Scientific Research (C), Principal Investigator

  • 胃発がんリスク亢進に繋がるピロリ菌感染宿主細胞の分子特性解析

    2016.04
    -
    2019.03

    MEXT,JSPS, Grant-in-Aid for Scientific Research, 津川 仁, Grant-in-Aid for Scientific Research (C), Principal Investigator

Awards 【 Display / hide

  • 第21回 日本ヘリコバクター学会 上原H. pylori優秀賞

    2015

    Type of Award: Awards of National Conference, Council and Symposium

  • 日本細菌学会黒屋奨学賞

    2014.03, 日本細菌学会

  • 日本細菌学会黒屋奨学賞

    2014

    Type of Award: Awards of National Conference, Council and Symposium

  • The 6th International Gastrointestinal Consensus Symposium (IGICS) Gold Medal Award

    2013

    Type of Award: International Academic Awards

  • 第19回 日本ヘリコバクター学会 上原H. pylori賞~最優秀賞~

    2013

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Courses Taught 【 Display / hide

  • BIOCHEMISTRY

    2019

 

Memberships in Academic Societies 【 Display / hide

  • 日本細菌学会

     
  • 日本薬学会

     
  • 日本ヘリコバクター学会

     
  • 日本分子生物学会

     
  • 日本癌学会

     

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Committee Experiences 【 Display / hide

  • 2016
    -
    Present

    評議員, 日本ヘリコバクター学会

  • 2017
    -
    Present

    学会賞選考委員, 日本ヘリコバクター学会