Development of order-made medicine for gastric cancer prevention

• Project/Area Number: 18390217
• Research Category: Grant-in-Aid for Scientific Research (B)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kobe University
• Principal Investigator: AZUMA Takeshi Kobe University, Department of Medicine, Professor (60221040)
• Co-Investigator(Kenkyū-buntansha): YOSHIDA Masaru Kobe University, Department of Medicine, Assistant Professor (00419475)
• Project Period (FY): 2006 – 2007
• Project Status: Completed (Fiscal Year 2007)
• Budget Amount: ¥17,020,000 (Direct Cost: ¥15,700,000、Indirect Cost: ¥1,320,000); Fiscal Year 2007: ¥5,720,000 (Direct Cost: ¥4,400,000、Indirect Cost: ¥1,320,000); Fiscal Year 2006: ¥11,300,000 (Direct Cost: ¥11,300,000)
• Keywords: Helicobacter pylori / Gastric cancer / CagA / Prevention

Research Abstract

H.pylori has been implicated in gastric carcinogenesis on the basis of various epidemiological studies. A working group of the WHO International Agency for Research on Cancer concluded that H. pylori is a group I carcinogen in human. After attachment of cagA-positive H. pylori to gastric epithelial cells, CagA is directly injected from the H. pylori into the cells via the type 4 secretion system and undergoes tyrosine phosphorylation in the host cells. Recently, we found the target protein of CagA in the gastric epithelial cells. It was src homology phosphatase 2 (SHP-2). SHP-2 is known to play an important positive role in the mitogenic signal transduction that is actively involved in the regulation of spreading, migration, and adhesion of cells. In this study, we developed cagA transgenic mice. To express CagA systemically and predominantly in the stomach in mice, cagA was connected downstream of the chicken β-actin promoter and the β-subunit gene promoter of mouse H^+ /K^+ -ATPase, respectively. By 72 weeks of age, 8.3% of the transgenic mice developed gastrointestinal polyps, and 1.8% of the mice developed gastrointestinal cancers. In addition, some transgenic mice using the chicken fl-actin promoter developed leukemia.
These findings suggest that CagA-SHP-2 pathway is important for carcinogenesis caused by H. pylori infection.

Research Products

• [Journal Article] Relationship of BRAF mutation, morphology, and apoptosis in early colorectal cancer. (2008)
  • Author(s): Yoshida S, Ikehara N, Aoyama N, Shirasaka D, Sakashita M, Semba S, Hasuo T, Miki I, Morita Y, Tamura T, Azuma T, Yokozaki H, Kasuga M
  • Journal Title: Int J Colorectal Dis 23(1) Pages: 7-13
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. (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: Proc Natl Acad Sci USA 105(3) Pages: 1003-1008
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Relationship of BRAY mutation, morphology, and apoptosis in early colorectal cancer (2008)
  • Author(s): Yoshida, S, Ikehara, N, Aoyama, N, Shirasaka, D, Sakashita, M, Semba, S, Hasuo, T, Mild, I, Morita, Y, Tamura, T, Azuma, T, Yokozaki, H, Kasuga, M
  • Journal Title: Int J Colorectal Dis 23(1) Pages: 7-13
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Transgenic expression of Helicobacter pyloh CagA induces gastrointestinal and hematopoietic neoplasms in mouse (2008)
  • Author(s): Ohnishi, N, Yuasa, H, Tanaka, S, Sawa, H, Miura, M, Matsui, A, Higashi, H, Musashi, M, Iwabuchi, K, Suzuki, M, Yamada, Azuma, T, Hatakeyama, M
  • Journal Title: Proc Natl Acad Sci USA 105(3) Pages: 1003-1008
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Transgenic expression of Helicobacter pylori CagA induces gastrointestinal and hematopoietic neoplasms in mouse. (2008)
  • Author(s): Ohnishi N
  • Journal Title: Proc Natl Acad Sci USA 105 Pages: 1003-1008
  • Peer Reviewed
• [Journal Article] Deregulation of beta-catenin signal by Helicobacter pylori CagA requires the CagA-multimerization sequence. (2008)
  • Author(s): Kurashima Y
  • Journal Title: Int J Cancer 122 Pages: 823-831
  • Peer Reviewed
• [Journal Article] Helicobacter pylori CagA targets PAR-1/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
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. (2007)
  • Author(s): Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, Morisawa T, Azuma T, Okazaki I, Honjo T, Chiba T
  • Journal Title: Nat Med 13 Pages: 470-476
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal trans differentiation 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 RM Jr, Azuma T, Hatakeyama M
  • Journal Title: Oncogene 26 Pages: 4617-4626
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Role of metallothionein in Helicobacter pylori-positive gastric mucosawith or without early gastric cancer and the effect on its expressionafter eradication therapy. (2007)
  • Author(s): Mitani T, Shirasaka D, Aoyama N, Miki I, Morita Y, Ikehara N, Matsuinoto Y, Okuno T, Toyoda M, Miyachi H, Yoshida S, Chayahara N, Hori J, Tamura T, Azuma, T, Kasuga M
  • Journal Title: Gastroenterol Hepatol [Epub aheadof print]
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] East Asian-type Helicobacter pylori cytotoxin-associated gene A protein has a more significant effect on growth of rat gastric mucosal cells than the Western type. (2007)
  • Author(s): Fu HY, Asahi K, Hayashi Y, Eguchi H, Murata H, Tsujii M, Tsuji S, Azuma T, Kawano S
  • Journal Title: Gastroenterol Hepatol 22 Pages: 355-362
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Pancreatic arteriovenous malformation combined with portal thrombosis. (2007)
  • Author(s): Takemoto I, Tsuda M, Yano Y, Miyazaki H, Yamada H, Azuma T, Maeda S, Nakajima T, Kasuga M
  • Journal Title: Intern Med 46(5) Pages: 233-6
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Japanese case of hepatitis B virus genotypes C/D hybrid. (2007)
  • Author(s): Yano Y, Truong BX. Seo Y, Kato H, Miki A, Tanaka Y, Mizokami M, Kagawa A, Miyazaki H. Kasuea M, Azuma T, Hapashi Y
  • Journal Title: Hepatol Res 37(12) Pages: 1095-1099
  • NAID: 10019796558
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Variations in the core promoter/pre-core region in HBV genotype C in Japanese and Northern Vietnamese patients. (2007)
  • Author(s): Truong BX, Yano Y, Seo Y, Phuong TM, Tanaka Y, Kato H, Miki A, Utsurni T, Azuma T, Trach NK, Mizokami M, Hayashi Y, Kasuga M
  • Journal Title: J Med Virol 79(9) Pages: 1293-1304
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Prescription of nonsteroidal anti-inflammatory drugs and co-prescribeddrugs for mucosal protection: analysis of the present status based onquestionnaires obtained from orthopedists in Japan. (2007)
  • Author(s): Tsumura H, Tamura I, Tanaka H, Chinzei R, Ishida T, Masuda A, Shiomi H, Morita Y, Yoshida M, Kutsumi H, Inokuchi H, Doita M, Kurosaka M, Azuma T
  • Journal Title: Intern Med 46(13) Pages: 927-931
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Favorable genetic polymorphisms predictive of clinical outcome of chemoradiotherapy for stage II/III esophageal squamous cellcarcinoma in Japanese. (2007)
  • Author(s): Okuno T, Tamura T, Yamamori M, Chayahara N, Yamada T, Miki I, Okamura N, Kadowaki Y, Shirasaka D, Aoyama N, Nakamura T, Okumura K, Azuma T, Kasuga M, Sakaeda T
  • Journal Title: Am J Clin Oncol 30(3) Pages: 252-257
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Changing antimicrobial susceptibility epldemiology of Helicobacter pylori strains in Japan between 2002 and 2005. (2007)
  • Author(s): Kobayashi I, Murakami K, Kato M, Kato S, Azuma T, Takahashi S, Uemura N, Katsuyama T, Fukuda Y, Haruma K, Nasu M, Fujioka T
  • Journal Title: J Clin Minrobiol 45(12) Pages: 4006-4010
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Helicobacter pylori CagA targets PAR-1/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
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium (2007)
  • Author(s): Matsumoto, Y, Marusawa, H, Kinoshita, K, Endo, Y, Kou, T, Morisawa, T, Azuma, T, Okazaki, I, Honjo, T, Chiba, T
  • Journal Title: Nat Med 13 Pages: 470-476
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal trans differentiation 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, RM, Jr, Azuma, T, Hatakeyama, M
  • Journal Title: Oncogene 26 Pages: 4617-4626
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Role of metallothionein in Helicobacter pylori-positive gastric mucosa with or without early gastric cancer and the effect on its expression after eradication therapy (2007)
  • Author(s): Mitani, T, Shirasaka, D, Aoyama, N, Miki, I, Morita, Y, Ikehara, N, Matsumoto, Y, Okuno, T, Toyoda, M, Miyachi, H, Yoshida, S, Chayahara, N, Hon, J, Tamura, T, Azuma, T, Kasuga, M
  • Journal Title: J Gastroenterol Hepatol 27(Epub ahead of print)
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] East Asian-type Helicobacter pylori cytotoxin-associated gene A protein has a more significant effect on growth of rat gastric mucosal cells than the Western type (2007)
  • Author(s): Fu, HY, Asahi, K, Hayashi, Y, Eguchi, H, Murata, H, Tsujii, M, Tsuji, S, Azuma, T, Kawano, S
  • Journal Title: J Gastroenterol Hepatol 22 Pages: 355-362
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Pancreatic arteriovenous malformation combined with portal thrombosis (2007)
  • Author(s): Takemoto, I, Tsuda, M, Yano, Y, Miyazaki, H, Yamada, H, Azuma, T, Maeda, S, Nakajima, T, Kasuga, M
  • Journal Title: Intern Med 46(5) Pages: 233-6
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Japanese case of hepatitis B virus genotypes C/D hybrid (2007)
  • Author(s): Yano, Y, Truong, BX, Seo, Y, Kato, H, Mild, A, Tanaka, Y, Mizokami, M, Kagawa, A, Miyazaki, H, Kasuga, M, Azuma, T, Hayashi, Y
  • Journal Title: Hepatol Res 37(12) Pages: 1095-1099
  • NAID: 10019796558
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Variations in the core promoter/pre-core region in HBV genotype C in Japanese and Northern Vietnamese patients (2007)
  • Author(s): Truong, BX, Yano, Y, Seo, Y, Phuong, TM, Tanaka, Y, Kato, H, Mild, A, Utsumi, T, Azuma, T, Trach, NK, Mizokami, M, Hayashi, Y, Kasuga, M
  • Journal Title: J Med Virol 79(9) Pages: 1293-1304
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Prescription of nonsteroidal anti-inflammatory drugs and co-prescribed drugs for mucosal protection: analysis of the present status based on questionnaires obtained from orthopedists in Japan (2007)
  • Author(s): Tsumura, H, Tamura, I, Tanaka, H, Chinzei, R, Ishida, T, Masuda, A, Shiomi, H, Morita, Y, Yoshida, M, Kutsumi, H, Inokuchi, H, Doita, M, Kurosaka, M, Azuma, T
  • Journal Title: Intern Med 46(13) Pages: 927-931
  • NAID: 130000076144
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Favorable genetic polymorphisms predictive of clinical outcome of chemoradiotherapy for stage II/III esophageal squamous cell carcinoma in Japanese (2007)
  • Author(s): Okuno, T, Tamura, T, Yamamori, M, Chayahara, N, Yamada, T, Mild, I, Okamura, N, Kadowaki, Y, Shirasaka, D, Aoyama, N, Nakamura, T, Okumura, K, Azuma, T, Kasuga, M, Sakaeda, T
  • Journal Title: Am J Clin Oncol 30(3) Pages: 252-257
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Changing antimicrobial susceptibility epidemiology of Helicobacter pylori strains in Japan between 2002 and 2005 (2007)
  • Author(s): Kobayashi, I, Murakami, K, Kato, M, Kato, S, Azuma, T, Takahashi, S, Uemura, N, Katsuyama, T, Fukuda, Y, Haruma, K, Nasu, M, Fujioka, T
  • Journal Title: J Clin Minrobiol 45(12) Pages: 4006-4010
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Helicobacter pylori CagA targets PAR-1/MARK kinase to disrupt epithelial cell polarity. (2007)
  • Author(s): Saadat I
  • Journal Title: Nature 447 Pages: 330-333
  • Peer Reviewed
• [Journal Article] Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori Cag A. (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
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori Cag A (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
  • Description: 「研究成果報告書概要(欧文)」より
• [Journal Article] Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. (2006)
  • Author(s): Naito M
  • Journal Title: Gastroenterology 130 Pages: 1181-1190
• [Journal Article] Focal adhesion kinase is a substrate and downstreameffector of SHP-2 complexed with Helicobacter pylori CagA. (2006)
  • Author(s): TsuTsumi R
  • Journal Title: Mol Cell Biol 26 Pages: 261-276
• [Journal Article] Relationship between the diversity of the cagA gene of Helicobacter pylori and gastric cancer in Okinawa, Japan. (2006)
  • Author(s): Satomi S
  • Journal Title: J Gastroenterol 41 Pages: 668-673
• [Journal Article] Structural basis and functional consequence of Helicobacter pylori CagA multimerization in cells. (2006)
  • Author(s): Ren S
  • Journal Title: J Biol Chem 281 Pages: 32344-32352
• [Journal Article] Blumberg RS, Azuma T. Fc {gamma} receptor regulation of citrobacter rodentium infection.
  • Author(s): Masuda A, Yoshida M, Shiomi H, Ikezawa S, Takagawa T, Tanaka H, Chinzei R, Ishida T, Morita Y, Kutsumi H, Inokuchi H, Wang S, Kobayashi K, Mizuno S, Nakamura A, Takai T, Blumberg RS, Azuma T
  • Journal Title: Infect Immun (in press)
  • Description: 「研究成果報告書概要(和文)」より
  • Peer Reviewed
• [Journal Article] Fc{gamma} receptor regulation of citrobacter rodentium infection
  • Author(s): Masuda, A, Yoshida, M, Shiomi, H, Ikezawa, S, Takagawa, T, Tanaka, H, Chinzei, R, Ishida, T, Morita, Y, Kutsumi, H, Inokuchi, H, Wang, S, Kobayashi, K, Mizuno, S, Nakamura, A, Takai, T, Blumberg, RS, Azuma, T
  • Journal Title: Infect Immun (in press)
  • Description: 「研究成果報告書概要(欧文)」より
• [Patent(Industrial Property Rights)] 特許 (2006)
  • Inventor(s): 東 健, 楠本正博
  • Industrial Property Rights Holder: 神戸大学, 東洋紡績株式会社
  • Industrial Property Number: 2006-354458
  • Filing Date: 2006-12-28