Mechanism and regulation of gastric carcinogenesis caused by Helicobacter pylori infection

2009 Fiscal Year Final Research Report

• Project/Area Number: 17013001
• Research Category: Grant-in-Aid for Scientific Research on Priority Areas
• Allocation Type: Single-year Grants
• Review Section: Biological Sciences
• Research Institution: Hokkaido University
• Principal Investigator: HATAKEYAMA Masanori Hokkaido University, 大学院・医学系研究科, 教授 (40189551)
• Project Period (FY): 2005 – 2009
• Keywords: ヘリコバクター・ピロリ / CagA / トランスジェニックマウス / 胃がん / 血液がん

Research Abstract

We identified that, upon delivery into host gastric epithelial cells, Helicobacter pylori virulence factor CagA binds to a human oncoprotein SHP-2 phosphatase and PAR1/MARK cell polarity regulator to perturb their activities, thereby causing cellular dysfunction that lead to malignant transformation. We also generated transgenic mice that express the H. pylori cagA gene and confirmed that CagA is the first bacterium-derived oncoprotein. Furthermore, we delineated the relationship between the structural polymorphism and the degree of oncogenic potential of CagA.

Research Products

• [Journal Article] Helicobacter pylor CagA activates NF-kB by targeting TAK1 for TRAF6-mediated K63-ubiquitination. (2009)
  • Author(s): Lamb, A., Yang, X-D., Nicole, Tsang., Y-H., Li, J-D., Higashi, H., Hatakeyama, M., Peek, R.M., Blanke, S. R, Chen, L-F.
  • Journal Title: EMBO Rep. 10 Pages: 1242-1249
  • Peer Reviewed
• [Journal Article] Differential oncogenic potential of geographically distinct Helicobacter pylori CagA isoforms in mice. (2009)
  • Author(s): Miura, M., Ohnishi, N., Tanaka, S., Yanagiya, K, Hatakeyama, M.
  • Journal Title: Int. J. Cancer 125 Pages: 2497-2504
  • Peer Reviewed
• [Journal Article] Role of Partitioning - defective 1/Microtubule affinity-regulating kinases in the morphogenetic activity of Helicobacter pylori CagA. (2009)
  • Author(s): Lu, H., Murata-Kamiya, N., Saito, Y, Hatakeyama, M.
  • Journal Title: J. Biol. Chem. 284 Pages: 23024-23036
  • Peer Reviewed
• [Journal Article] Helicobacter pylori CagA causes mitotic impairment and induces chromosomal instability. (2009)
  • Author(s): Umeda, M., Murata-Kamiya, N., Saito Y., Ohba, Y., Takahashi, M, Hatakeyama, M.
  • Journal Title: J. Biol. Chem. 284 Pages: 22166-22172
  • Peer Reviewed
• [Journal Article] Stability of Helicobacter pylori CagA oncoprotein in human gastric epithelial cells. (2009)
  • Author(s): Ishikawa, S., Ohta, T, Hatakeyama, M.
  • Journal Title: FEBS Letters 583 Pages: 2414-2418
  • Peer Reviewed
• [Journal Article] Helicobacter pylori and gastric carcinogenesis. (2009)
  • Author(s): Hatakeyama, M.
  • Journal Title: J. Gastroenterol. 44 Pages: 239-248
  • Peer Reviewed
• [Journal Article] Helicobacter pylori VacA-induced inhibition of GSK3 through the PI3K/Akt signaling pathway. (2009)
  • Author(s): Nakayama, M., Hisatsune, J., Yamasaki, E., Isomoto, H., Kurazono, H., Hatakeyama, M., Azuma, T., Yamaoka, Y., Yahiro, K., Moss, J, Hirayama, T.
  • Journal Title: J. Biol. Chem. 284 Pages: 1612-1619
  • Peer Reviewed
• [Journal Article] Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA. (2008)
  • Author(s): Hatakeyama, M.
  • Journal Title: Oncogene 27 Pages: 7047-7054
  • Peer Reviewed
• [Journal Article] Structural and functional diversity in the PAR1b/MARK2-binding region of Helicobacter pylori CagA. (2008)
  • Author(s): Lu, H., Saito, Y., Umeda, M., Murata-Kamiya, N., Zhang, H., Higashi, H, Hatakeyama, M.
  • Journal Title: Cancer Science 99 Pages: 2004-2011
  • Peer Reviewed
• [Journal Article] Anti-tumor activity of ESX1 on cancer cells harboring oncogenic K-ras mutation. (2008)
  • Author(s): Nakajima, J., Ishikawa, S., Hamada, J., Yanagihara, M., Koike, T, Hatakeyama, M.
  • Journal Title: Biochem. Biophys. Res. Commun. 370 Pages: 189-194
  • Peer Reviewed
• [Journal Article] Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. Proc. (2008)
  • Author(s): Ohnishi, N., Yuasa, H., Tanaka, S., Sawa, H., Miura, M., Matsui, A., Higashi, H., Musashi, M., Iwabuchi, K., Suzuki, M., Yamada, G., Azuma, T, Hatakeyama, M.
  • Journal Title: Natl. Acad. Sci. USA 105 Pages: 1003-1008
  • Peer Reviewed
• [Journal Article] SagA of CagA in Helicobacter pylori pathogenesis. (2008)
  • Author(s): Hatakeyama, M.
  • Journal Title: Cur. Opin. Microbiol. 11 Pages: 30-37
  • Peer Reviewed
• [Journal Article] Isolation of a distinct class of gain-of-function SHP-2 muntants with oncogenic RAS-like transforming activity from solid tumors. (2008)
  • Author(s): Miyamoto, D., Miyamoto, M., Takahashi, A., Yomogita, Y., Higashi, H., Kondo, S, Hatakeyama, M.
  • Journal Title: Oncogene 27 Pages: 3508-3515
  • Peer Reviewed
• [Journal Article] Deregulation of b-catenin signal by Helicobacter pylori CagA requires the CagA - multimerization sequence. (2008)
  • Author(s): Kurashima, Y., Murata-Kamiya, N., Kikuchi, K., Higashi, H., Azuma, T., Kondo, S, Hatakeyama, M.
  • Journal Title: International Journal of Cancer 122 Pages: 823-831
  • Peer Reviewed
• [Journal Article] H. pylori CagAによる細胞がん化のメカニズム (2008)
  • Author(s): 畠山昌則.
  • Journal Title: 医学のあゆみ 224 Pages: 704-710
• [Journal Article] Helicobacter pylori CagA targets PAR1 / MARK kinase to disrupt epithelial cell polarity. (2007)
  • Author(s): Saadat, I., Higashi, H., Obuse, C., Umeda, M., Murata-Kamiya, N., Saito, Y., Lu, H., Ohnishi, N., Azuma, T., Suzuki, A., Ohno, S, Hatakeyama, M.
  • Journal Title: Nature 447 Pages: 330-333
  • Peer Reviewed
• [Journal Article] Helicobacter pylori CagA interacts with E-cadherin and deregulates the b-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. (2007)
  • Author(s): Murata-Kamiya, N., Kurashima, Y., Teishikata, Y., Yamahashi, Y., Saito, Y., Higashi, H., Aburatani, H., Akiyama, T., Peek, R.M., Jr., Azuma, T, Hatakeyama, M.
  • Journal Title: Oncogene 26 Pages: 4617-4626
  • Peer Reviewed
• [Journal Article] ヘリコバクター・ピロリCagAによる上皮細胞極性破壊と細胞がん化のカップリング (2007)
  • Author(s): 畠山昌則.
  • Journal Title: 細胞工学 27 Pages: 172-177
• [Journal Article] ヘリコバクター・ピロリと胃がん (2007)
  • Author(s): 畠山昌則.
  • Journal Title: 日本消化器病学会雑誌-総説 104 Pages: 635-643
• [Journal Article] Structural basis and functional consequence of Helicobacter pylori CagA multimerization in Cells. (2006)
  • Author(s): Ren, S., Higashi, H., Lu, H., Azuma, T, Hatakeyama, M.
  • Journal Title: J. Biol. Chem. 281 Pages: 32344-32352
  • Peer Reviewed
• [Journal Article] The role of Helicobacter pylori CagA in gastric carcinogenesis. (2006)
  • Author(s): Hatakeyama, M.
  • Journal Title: Int. J. Hematol. 84 Pages: 301-308
  • Peer Reviewed
• [Journal Article] Development of a novel method to detect Helicobacter pylori cagA genotype from paraffin - embedded materials: comparison between patients with duodenal ulcer and gastric cancer in young Japanese. (2006)
  • Author(s): Ueda, H., Ito, M., Eguchi, H., Tanaka, S., Yoshihara, M., Haruma, K., Hatakeyama, M, Chayama, K.
  • Journal Title: Digestion 73 Pages: 47-53
  • Peer Reviewed
• [Journal Article] Pathogenesis of Helicobacter pylori infection. (2006)
  • Author(s): Hatakeyama, M, Brzozowski, T.
  • Journal Title: Helicobacter 11,Suppl1 Pages: 14-20
  • Peer Reviewed
• [Journal Article] Influence of EPIYA - repeat polymorphism on the phosphorylation- dependent biological activity of Helicobacter pylori CagA. (2006)
  • Author(s): Naito, M., Yamazaki, T., Tsutsumi, R., Higashi, H., Onoe, K., Yamazaki, S., Azuma, T, Hatakeyama, M.
  • Journal Title: Gastroenterology 130 Pages: 1181-1190
  • Peer Reviewed
• [Journal Article] Helicobacter pylori CagA-a bacterial intruder conspiring gastric carcinogenesis. (2006)
  • Author(s): Hatakeyama, M.
  • Journal Title: Int. J. Cancer 119 Pages: 1217-1223
  • Peer Reviewed
• [Journal Article] Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA. (2006)
  • Author(s): Tsutsumi, R., Takahashi, A., Azuma, A., Higashi, H, Hatakeyama, M.
  • Journal Title: Mol. Cell. Biol. 26 Pages: 261-276
  • Peer Reviewed
• [Journal Article] Helicobacter pylori CagA - a new paradigm for bacterial carcinogenesis. (2005)
  • Author(s): Hatakeyama, M., Higashi, H.
  • Journal Title: Cancer Sci. 96 Pages: 835-843
  • Peer Reviewed
• [Journal Article] Downregulation of cyclin-dependent kinase inhibitor; p57(kip2), is involved in the cell cycle progression of vascular smooth muscle cells. (2005)
  • Author(s): Nakano, N., Urasawa, K., Takagi, Y., Saito, T., Kaneta, S., Ishikawa, S., Higashi, H., Tsutsui, H., Hatakeyama, M, Kitabatake, A.
  • Journal Title: Biochem. Biophys. Res. Commun. 338 Pages: 1661-1667
  • Peer Reviewed
• [Journal Article] Paired-like homeoprotein ESXR1 acts as a sequence-specific transcriptional repressor of the human K-ras gene. (2005)
  • Author(s): Yanagihara, M., Ishikawa, S., Naito, M., Nakajima, J., Aburatani, H, Hatakeyama, M.
  • Journal Title: Oncogene 24 Pages: 5878-5887
  • Peer Reviewed
• [Journal Article] Functional antagonism between Helicobacter pylori CagA and vacuolating toxin VacA in control of the NFAT signaling pathway in gastric epithelial cells. (2005)
  • Author(s): Yokoyama, K., Higashi, H., Ishikawa, S., Fujii, Y., Kondo, S., Kato, H., Azuma, T., Wada, A., Hirayama, T., Aburatani, H, Hatakeyama, M.
  • Journal Title: Proc. Natl. Acad. Sci. USA 102 Pages: 9661-9666
  • Peer Reviewed
• [Journal Article] EPIYA motif is a membrane-targeting singnal of Helicobacter pylori virulence factor CagA in mammalian cells. (2005)
  • Author(s): Higashi, H., Yokoyama, K., Fujii, Y., Ren, S., Yuasa, H., Saadat, I., Murata-Kamiya, N., Azuma, T, Hatakeyama, M.
  • Journal Title: J. Biol. Chem. 280 Pages: 23130-23137
  • Peer Reviewed
• [Journal Article] Activation of beta-catenin by carcinogenic Helicobacter pylori. Proc. (2005)
  • Author(s): Franco, A.T., Israel, D.A., Washington, M.K., Krishna, U., Fox, J.G., Rogers, A.B., Neish, A.S., Collier-Hyams, L., Perez-Perez, G.I., Hatakeyama, M., Whitehead, R., gaus, K., O'brien, D.P., Romero-Gallo, J., Peek, R.M., Jr.
  • Journal Title: Natl. Acad. Sci. USA 102 Pages: 10646-10651
  • Peer Reviewed
• [Journal Article] Distinct diversity of vacA, cagA, and cagE genes of Helicobacter pylori associated with peptic ulcer in Japan. (2005)
  • Author(s): Yamazaki, S., Yamakawa, A., Okuda, T., Ohtani, M., Suto, H., Ito, Y., Yamazaki, Y., Keida, Y., Higashi, H., Hatakeyama, M, Azuma, T.
  • Journal Title: J. Clin. Microbiol. 43 Pages: 3906-3916
  • Peer Reviewed
• [Journal Article] Identification of Helicobacter pylori and the cagA genotype in gastric biopsies using higly sensitive real-time PCR as a new diagnostic tool. (2005)
  • Author(s): Yamazaki, S., Kato, S., Matsukura, N., Ohtani, M., Ito, Y., Suto, H., Yamazaki, Y., Yamakawa, A., Tokudome, S., Higashi, H., Hatakeyama, M, Azuma, T.
  • Journal Title: FEMS Immunol. Med. Microbiol. 44 Pages: 261-268
  • Peer Reviewed
• [Journal Article] H. pylori感染による胃発がん機序 (2005)
  • Author(s): 畠山昌則
  • Journal Title: 消化器科 41 Pages: 389-397
• [Journal Article] Helicobacter pylori CagA -SHP-2相互作用と胃がん (2005)
  • Author(s): 畠山昌則
  • Journal Title: 日本臨床 63,Suppl11 Pages: 48-52
• [Presentation] Oncogenic mechanism of Helicobacter pylori CagA (2010)
  • Author(s): 畠山昌則
  • Organizer: ドイツ衛生学・微生物学会(DGHM)
  • Place of Presentation: Convention Center Hanover, Hanover, Germany.
  • Year and Date: 2010-03-30
• [Presentation] New Approaches to Cancer Immunotherapy (2010)
  • Author(s): 畠山昌則
  • Organizer: 日米がん合同会議(JCA-AACR)
  • Place of Presentation: Hilton Waikoloa Village, Waikoloa, Hawaii.
  • Year and Date: 2010-02-05
• [Presentation] Animal Model of Carcinogenesis (2009)
  • Author(s): 畠山昌則
  • Organizer: 2nd Gyoungnam Regional Cancer Center Symposium
  • Place of Presentation: Gyeongsang National University Hospital, Jinju, Krea.
  • Year and Date: 2009-11-19
• [Presentation] Gastric cancer - a paradigm of bacterial carcinogenesis (2009)
  • Author(s): 畠山昌則
  • Organizer: French- Japanese Workshop in Life Sciences
  • Place of Presentation: CNRS. Campas Gerard-Megie, Paris, France.
  • Year and Date: 2009-09-22
• [Presentation] Does cag cause cancer and if so how? (2008)
  • Author(s): 畠山昌則
  • Organizer: UEGW Vienna 2008/16th United European gastroenterology Week
  • Place of Presentation: Austria Center Vienna, Vienna, Austria.
  • Year and Date: 2008-10-21
• [Presentation] The role of SHP2 phosphatase in H. pylori-mediated gastric carcinogenesis (2008)
  • Author(s): 畠山昌則
  • Organizer: 2008 FASEB Summer Research Conferences
  • Place of Presentation: Snowmass Village, Colorado, USA.
  • Year and Date: 2008-07-15
• [Presentation] The role of SHP2 phosphatase in H. pylori-mediated gastric carcinogenesis (2008)
  • Author(s): 畠山昌則
  • Organizer: IMBA主催生物学セミナーシリーズ
  • Place of Presentation: Vienna Biocenter, Vienna, Austria.
  • Year and Date: 2008-06-12
• [Presentation] Helicobacter pylori and molecular pathogenesis (2008)
  • Author(s): 畠山昌則
  • Organizer: AACR Annual meeting 2008
  • Place of Presentation: San Diego convention center, San Diego, USA.
  • Year and Date: 2008-04-14
• [Presentation] H. pylori and gastric carcinogenesis (2008)
  • Author(s): 畠山昌則
  • Organizer: The Asia - Africa International Network Symposium of JSPS Asia and Africa Science Platform Program and The Fourth LiverCare Center Symposium
  • Place of Presentation: Charoen Thani Hotel, Khon Kaen, Thailand.
  • Year and Date: 2008-02-20
• [Presentation] Microbial-host interactions in infectious cancer (2007)
  • Author(s): 畠山昌則
  • Organizer: International Symposium -Dysregulation of cell Communication in immune and Neuronal Cells
  • Place of Presentation: Otto von Guericke University, Magdeburg, Germany.
  • Year and Date: 2007-11-29
• [Presentation] The role of Helicobacter pylori CagA in gastric carcinogenesis (2007)
  • Author(s): 畠山昌則
  • Organizer: Seoul International Digestive Disease Symposium 2007(SIDDS 2007)
  • Place of Presentation: Seoul University, Seoul, Korea.
  • Year and Date: 2007-11-22
• [Presentation] Oncogenic protenital of the Helicobacter pylori CagA (2007)
  • Author(s): 畠山昌則
  • Organizer: Seoul International Digestive Disease Symposium 2007(SIDDS 2007)
  • Place of Presentation: Seoul University, Seoul, Korea.
  • Year and Date: 2007-11-21
• [Presentation] The role of Helicobacter pylori CagA in gastric carcinogenesis (2007)
  • Author(s): 畠山昌則
  • Organizer: The 19th FAOBMB Seoul Conference
  • Place of Presentation: COEX Center in Seoul, Seoul, Korea.
  • Year and Date: 2007-05-29
• [Presentation] Activation of β-catenin signal by Helicobacter pylori CagA (2006)
  • Author(s): 畠山昌則
  • Organizer: European Helicobacter Study group International Workshop: Microbiological Aspects and Virulence Factors
  • Place of Presentation: ブロツワフ大学講堂, Wroclaw, Poland.
  • Year and Date: 2006-09-09
• [Presentation] Reciprocal regulation of NFAT transcription factors by the two major Helicobacter pylori virulence factors, CagA and VacA (2005)
  • Author(s): 畠山昌則
  • Organizer: European Helicobacter Study group International Workshop
  • Place of Presentation: Copenhagen, Denmark.
  • Year and Date: 2005-10-14
• [Book] バイオとナノの融合II新生命科学の応用(第22章) (2007)
  • Author(s): 畠山昌則
  • Total Pages: 317-342
  • Publisher: 北海道大学発行
• [Book] 別冊・医学のあゆみ消化管疾患Ver. 3-state of arts. I.(消化管(食道・胃・腸)) (2006)
  • Author(s): 畠山昌則
  • Total Pages: 44-47
  • Publisher: 医歯薬出版(株)
• [Book] がん研究の今-1.(笹月健彦、野田哲生編, 発がんの分子機構と防御) (2006)
  • Author(s): 畠山昌則
  • Total Pages: 47-62
  • Publisher: 東大出版会
• [Book] がんのシグナル伝達がわかる(山本雅、仙波憲太郎編, わかる実験医学シリーズ) (2005)
  • Author(s): 大西なおみ, 畠山昌則
  • Total Pages: 35-42
  • Publisher: 羊土社
• [Remarks]
  • URL: http://www.microbiol.m.u-tokyo.ac.jp/
• [Patent(Industrial Property Rights)] ヒトK-ras遺伝子転写抑制剤 (2005)
  • Inventor(s): 畠山昌則
  • Industrial Property Rights Holder: 北海道大学
  • Industrial Property Number: 特許・特許第2006-542246号
  • Filing Date: 2005-07-01
• [Patent(Industrial Property Rights)] ヒトK-ras遺伝子転写抑制剤 (2005)
  • Inventor(s): 畠山昌則
  • Industrial Property Rights Holder: 北海道大学
  • Industrial Property Number: 国際特許・特許11/666520号
  • Filing Date: 2005-07-01
• [Patent(Industrial Property Rights)] ヒトK-ras遺伝子転写抑制剤 (2005)
  • Inventor(s): 畠山昌則
  • Industrial Property Rights Holder: 北海道大学
  • Industrial Property Number: 国際特許・特許2592351号
  • Filing Date: 2005-07-01