Induction of cardiovascular lesions by Helicobacter pylori

• Project/Area Number: 16K15273
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: Bacteriology (including mycology)
• Research Institution: The University of Tokyo
• Principal Investigator: Hatakeyama Masanori 東京大学, 大学院医学系研究科(医学部), 教授 (40189551)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2017: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000); Fiscal Year 2016: ¥2,470,000 (Direct Cost: ¥1,900,000、Indirect Cost: ¥570,000)
• Keywords: 毒素・エフェクター / ピロリ菌 / CagA / エクソソーム / ヘリコバクター・ピロリ / 血管病変 / トランスジェニックマウス / 細菌 / 循環器・高血圧

Outline of Final Research Achievements

Recent epidemiological studies suggest the relationship between cardiovascular diseases such as angina pectoris and myocardial infarction and chronic infection with H. pylori producing the oncogenic effector protein CagA. Following injection into gastric epithelial cells, a fraction of CagA proteins are incorporated into exosomes, which are secreted from the epithelial cells into the general circulation. This suggests that CagA reaches vascular endothelial cells via exosomes. We found in this work that, in vascular endothelial cells, CagA induces EMT-like morphological transformation and elevated cell motility in its tyrosine phosphorylation-dependent manner. We also succeeded in establishing genetically engineered mice that specifically express CagA in vascular endothelial cells or gastrointestinal cells, which provide an excellent in vivo model system in investigating the role of H. pylori CagA in cardiovascular lesions.

Research Products

• [Journal Article] Transcriptional co-activator functions of YAP and TAZ are inversely regulated by tyrosine phosphorylation status of Parafibromin. (2018)
  • Author(s): Tang, C., Takahashi-Kanemitsu, A., Kikuchi, I., Ben, C. and Hatakeyama, M.
  • Journal Title: iScience Volume: 1 Pages: 1-15
  • DOI: 10.1016/j.isci.2018.03.023
  • Peer Reviewed
• [Journal Article] Differential mechanisms for SHP2 binding and activation are exploited by geographically distinct Helicobacter pylori CagA Oncoproteins. (2017)
  • Author(s): Hayashi, H., Senda, M., Suzuki, N., Nishikawa, H., Ben, C., Tang, C., Nagase, L., Inoue, K., Senda, T. and Hatakeyama, M.
  • Journal Title: Cell Rep Volume: 20 Issue: 12 Pages: 2876-2890
  • DOI: 10.1016/j.celrep.2017.08.080
  • Peer Reviewed / Open Access
• [Journal Article] Sequence Polymorphism and Intrinsic Structural Disorder as Related to Pathobiological Performance of the Helicobacter pylori CagA Oncoprotein (2017)
  • Author(s): Nishikawa Hiroko、Hatakeyama Masanori
  • Journal Title: Toxins Volume: 9 Issue: 4 Pages: 136-136
  • DOI: 10.3390/toxins9040136
  • Peer Reviewed / Open Access
• [Journal Article] A sour relationship between BabA and Lewis b. (2017)
  • Author(s): Hatakeyama, M.
  • Journal Title: Cell Host Microbe Volume: 21 Issue: 3 Pages: 318-320
  • DOI: 10.1016/j.chom.2017.02.014
  • Peer Reviewed
• [Journal Article] Structure and function of <i>Helicobacter pylori</i> CagA, the first-identified bacterial protein involved in human cancer (2017)
  • Author(s): Hatakeyama, M.
  • Journal Title: Proceedings of the Japan Academy, Series B Volume: 93 Issue: 4 Pages: 196-219
  • DOI: 10.2183/pjab.93.013
  • NAID: 130006770746
  • ISSN: 0386-2208, 1349-2896
  • Peer Reviewed
• [Journal Article] Enhanced expression of PKM2 is involved in the gastric cancer development via regulating cancer specific metabolism. (2017)
  • Author(s): Shiroki T, Yokoyama M, Tanuma N, Maejima R, Tamai K, Yamaguchi K, Oikawa T, Noguchi T, Miura K, Fujiya T, Shima H, Sato I, Kamiya N, Hatakeyama M, Iijima K, Shimosegawa T and Satoh K.
  • Journal Title: Cancer Science Volume: 印刷中 Issue: 5 Pages: 931-940
  • DOI: 10.1111/cas.13211
  • Peer Reviewed / Open Access
• [Journal Article] Formation and functional analysis of specific tRNA granules caused by low-dose X-ray irradiation. (2017)
  • Author(s): Katano, A., Miyagawa, R., Kobayashi, R., Yamashita, H,, Morikawa, T., Sakumi, A., Tamari, Y., Kamiya, N., Hatakeyama, M., Fukayama, M., Kuni Ohtomo, K. and Nakagawa, K.
  • Journal Title: Bioimages Volume: 印刷中
  • Peer Reviewed
• [Journal Article] CEACAM6 is upregulated by Helicobacter pylori CagA and is a biomarker for early gastric cancer. (2016)
  • Author(s): Roy, R.K., Hoppe, M.M., Sharma, N., Srivastava, S., Tan, K.T., Yang, H., Voon, D.C., Pang, B., The, M., Murata-Kamiya, N., Hatakeyama, M., Samanta, A., Chang, Y.T., Ito, Y., Ho, K.Y., Tan, P., Soong, R., Koeffler, P.H., Yeoh, K.G. and Jeyasekharan, A.D.
  • Journal Title: Oncotarget Volume: 7 Issue: 34 Pages: 55290-55301
  • DOI: 10.18632/oncotarget.10528
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] The Helicobacter pylori cytotoxin CagA is essential for suppressing host heat shock protein expression (2016)
  • Author(s): Lang, B.
  • Journal Title: Cell Stress Chaperones Volume: 21 Issue: 3 Pages: 1-11
  • DOI: 10.1007/s12192-016-0680-x
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Helicovanter pylori VacA, acting through receptor tyrosine phosphatase is crucial for CagA phosphorylation in human duodenal carcinoma cell line AZ-521. (2016)
  • Author(s): Nakano, M., Yahiro, K., Yamazaki, E., Kurazono, H., Akada, J.K., Yamaoka, Y., Niidome, T., Hatakeyama, M., Suzuki, H., Yamamoto, T. Moss, J. and Hirayama, T.
  • Journal Title: Dis. Model Mech. Volume: 9 Issue: 12 Pages: 1473-1481
  • DOI: 10.1242/dmm.025361
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Dephosphorylated parafibromin is a transcriptional coactivator of the Wnt/Hedgehog/Notch pathways. (2016)
  • Author(s): Kikuchi I, Takahashi-Kanemitsu A, Sakiyama N, Tang C, Tang PJ, Noda S, Nakao K, Kassai H, Sato T, Aiba A, and Hatakeyama M.
  • Journal Title: Nat Commun Volume: 7 Issue: 1 Pages: 12887-12887
  • DOI: 10.1038/ncomms12887
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Impact of structural polymorphism for the Helicobacter pylori CagA oncoprotein on binding to polarity-regulating kinase PAR1b. (2016)
  • Author(s): Nishikawa, H., Hayashi, T., Arisaka, F., Senda, T., Hatakeyama, M.
  • Journal Title: Sci. Rep. Volume: 6 Issue: 1 Pages: 30031-30031
  • DOI: 10.1038/srep30031
  • Peer Reviewed / Open Access
• [Journal Article] Csk-mediated EPIYA phosphorylation of Pragmin creates a feed-forward Csk activation loop that promotes cell motility. (2016)
  • Author(s): Senda, Y., Murata-Kamiya, N. and Hatakeyama, M.
  • Journal Title: Cancer Sci. Volume: 107 Issue: 7 Pages: 972-980
  • DOI: 10.1111/cas.12962
  • Peer Reviewed / Open Access
• [Journal Article] <i><b>Helicobacter pylori</b></i><b> induces IL-1β protein through the inflammasome activation in differentiated macrophagic </b><b>cells </b> (2016)
  • Author(s): Kameoka, S.
  • Journal Title: Biomedical Research Volume: 37 Issue: 1 Pages: 21-27
  • DOI: 10.2220/biomedres.37.21
  • NAID: 130005128374
  • ISSN: 0388-6107, 1880-313X
  • Peer Reviewed / Open Access
• [Journal Article] Improvement of Helicobacter pylori CagA crystals by the multi-step soaking method (2016)
  • Author(s): Senda, M.
  • Journal Title: Cryst. Growth Des. Volume: 16 Issue: 3 Pages: 1565-1571
  • DOI: 10.1021/acs.cgd.5b01692
  • Peer Reviewed / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Host SHP1 phosphatase antagonizes Helicobacter pylori CagA and can be downregulated by EBV. (2016)
  • Author(s): Saju, P., Murata-Kamiya, N., Hayashi, T., Senda, Y., Nagase, L., Noda, S., Matusaka, K., Funata, S., Kunita, A., Urabe, M., Seto, Y., Fukayama, M., Kaneda, A., Hatakeyama, M.
  • Journal Title: Nature Microbiology Volume: 1 Issue: 4 Pages: 16026-16026
  • DOI: 10.1038/nmicrobiol.2016.26
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Determination of the catalytic activity of LEOPARD syndrome- associated SHP2 mutants toward parafibromin, a bona fide SHP2 substrate involved in Wnt signaling (2016)
  • Author(s): Saori Noda, Atsushi Takahashi, Takeru Hayashi, Sei-ichi Tanuma and Masanori Hatakeyama
  • Journal Title: Biochemical and Biophysical Research Communications Volume: 469 Issue: 4 Pages: 1133-1139
  • DOI: 10.1016/j.bbrc.2015.12.117
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Exosomes as nanocarriers for systemic delivery of the Helicobacter pylori virulence factor CagA (2016)
  • Author(s): Shimoda A, Ueda K, Nishiumi S, Murata-Kamiya N, Mukai SA, Sawada S, Azuma T, Hatakeyama M, Akiyoshi K
  • Journal Title: Scientific Reports Volume: 6 Issue: 1 Pages: 18346-18346
  • DOI: 10.1038/srep18346
  • NAID: 120005689168
  • Peer Reviewed / Open Access
• [Presentation] ヘリコバクター・ピロリによる異所性炎症誘導機構の解明 (2018)
  • Author(s): 畠山 昌則
  • Organizer: 北海道大学遺伝子病制御研究所セミナー
  • Invited
• [Presentation] Role of the Helicobacter pylori CagA oncoprotein in gastric carcinogenesis (2017)
  • Author(s): 畠山 昌則
  • Organizer: 第８９回日本胃癌学会総会
  • Place of Presentation: 広島国際会議場、広島市
  • Year and Date: 2017-03-09
  • Invited
• [Presentation] Collaboration between Helicobacter pylori CagA and Epstein-Barr virus in gastric carcinogenesis (2017)
  • Author(s): Hatakeyama,M.
  • Organizer: 19th International Conference on Emerging Infectious Diseases in the Pacific Rim
  • Place of Presentation: Novotel Ambassador Hotel Seoul Gangnam,Seoul
  • Year and Date: 2017-02-08
  • Int'l Joint Research / Invited
• [Presentation] Wnt,Hedgehog,Notch シグナルを細胞内で統合制御する機構 (2017)
  • Author(s): 畠山 昌則
  • Organizer: 北海道大学遺伝子病制御研究所セミナー
  • Place of Presentation: 北海道大学遺伝子病制御研究所、札幌市
  • Year and Date: 2017-01-20
  • Invited
• [Presentation] Synergy between EBV & H. pylori (2017)
  • Author(s): 畠山 昌則
  • Organizer: EHMSG 2017 XXXth International Workshop on Helicobacter and Microbiota in inflammation and Cancer
  • Int'l Joint Research / Invited
• [Presentation] がんの発症をうながす細菌叢の偏倚 (2017)
  • Author(s): 畠山 昌則
  • Organizer: 第76回日本癌学会学術総会
  • Invited
• [Presentation] Geographically distinct Helicobactor pylori Cage oncoprotein exploit differential mechanisms for SHP2 binding and activation (2017)
  • Author(s): 畠山 昌則
  • Organizer: The 3rd Japan-Taiwan Bilateral Conference on Protein Phosphatase
  • Int'l Joint Research / Invited
• [Presentation] 胃癌の病態解明から新しい治療へ (2017)
  • Author(s): 畠山 昌則
  • Organizer: 第108回日本消化器病学会中国支部例会
  • Invited
• [Presentation] Helicobactor Pylori in Gastric cancer (2017)
  • Author(s): 畠山 昌則
  • Organizer: Seoul International Gastic Forum 2017
  • Int'l Joint Research / Invited
• [Presentation] ピロリ菌感染を基盤とする胃癌発症機構 (2016)
  • Author(s): 畠山 昌則
  • Organizer: 日本消化器病学会関東支部第３４２回例会
  • Place of Presentation: 海運ビル、千代田区
  • Year and Date: 2016-12-03
  • Invited
• [Presentation] Parafibromin,a substrate of SHP2 is a transcriptional platform that integrates morphogen signling pathways (2016)
  • Author(s): Hatakeyama,M.
  • Organizer: 12th International Conference on Protein Phosphatase
  • Place of Presentation: 近畿大学、東大阪市
  • Year and Date: 2016-10-27
  • Int'l Joint Research / Invited
• [Presentation] Inactivation of the Helicobacter pylori CagA oncoprotein-A potential strategy for prevention of gastic cancer- (2016)
  • Author(s): Hatakeyama,M.
  • Organizer: The 75th AnnualMeeting of the Japanese Cancer Association,Symposium
  • Place of Presentation: パシフィコ横浜、横浜市
  • Year and Date: 2016-10-26
  • Invited
• [Presentation] ピロリ菌による胃発がん機構とその予防的介入 (2016)
  • Author(s): 畠山 昌則
  • Organizer: 翻訳後修飾プロテオミクス医療研究拠点の形成 第７回シンポジウム
  • Place of Presentation: 横浜情報文化センター・情文ホール、横浜市
  • Year and Date: 2016-10-26
  • Invited
• [Presentation] SHPIホスファターゼを介したピロリ菌CagAの発がん抑制活性とEBウイルスによるその解除 (2016)
  • Author(s): 畠山 昌則
  • Organizer: 第８９回日本生化学会大会シンポジウム
  • Place of Presentation: 仙台国際センター、仙台市
  • Year and Date: 2016-09-25
  • Invited
• [Presentation] Collaboration between Helicobacter pylori CagA and EBV in gastric carcinogenesis (2016)
  • Author(s): Hatakeyama,M.
  • Organizer: XXIXth International Workshop on the European Helicobacter & Microbiota in Inflammation and Cancer
  • Place of Presentation: Magdeburg,Germany
  • Year and Date: 2016-09-16
  • Int'l Joint Research / Invited
• [Presentation] SHP1 links Helicobacter pylori and Epstein-Barr virus in gastric carcinoegensis (2016)
  • Author(s): Hatakeyama,M.
  • Organizer: The 15th Awaji International forum of Infection and Immunity
  • Place of Presentation: 淡路夢舞台国際会議場、淡路市
  • Year and Date: 2016-09-08
  • Int'l Joint Research / Invited
• [Presentation] Oncogenic collaboration between Helicobacter pylori and Epstein-Barr virus in gastric carcinogenesis (2016)
  • Author(s): Hatakeyama,M.
  • Organizer: Singaoire Gastric Cancer Consortium 9th Annual Scientific Meeting
  • Place of Presentation: NUHS Auditorium,Singapore
  • Year and Date: 2016-07-21
  • Int'l Joint Research / Invited
• [Presentation] ピロリ菌がんタンパク質CagAによる胃はつがん機構 (2016)
  • Author(s): 畠山 昌則
  • Organizer: 第２７回三河感染・免疫研究会
  • Place of Presentation: ホテルアソシア豊橋、豊橋市
  • Year and Date: 2016-07-16
  • Invited
• [Presentation] ピロリ菌がんタンパク質CagA～「胃がん」から「全身病へ」～ (2016)
  • Author(s): 畠山 昌則
  • Organizer: 島根大学医学部セミナー
  • Place of Presentation: 島根大学医学部、出雲市
  • Year and Date: 2016-07-05
  • Invited
• [Book] Helicobacter pylori (2016)
  • Author(s): Senda, S. and Hatakeyama, M.
  • Publisher: Springer