Mechanism for inflammation-associated gastrointestinal carcinogenesis.

2008 Fiscal Year Final Research Report

• Project/Area Number: 18209027
• Research Category: Grant-in-Aid for Scientific Research (A)
• Allocation Type: Single-year Grants
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: CHIBA Tsutomu Kyoto University, 医学研究科, 教授 (30188487)
• Co-Investigator(Renkei-kenkyūsha): WATANABE Norihiko 京都大学, 医学研究科, 准教授 (50419446)
• Project Period (FY): 2006 – 2008
• Keywords: AID / 炎症 / 発癌 / 遺伝子変異 / H. pylori / REG蛋白

Research Abstract

炎症から消化器発癌に至る機序について研究を行い、HPからの胃癌発症では、ホストのTh1/Th2バランスが重要であり、IFNγ, IL6, 22などがregIαの発現を増強して発癌に関与していること、胃炎、胃癌の発症には小腸パイエル板が必須であること、さらにHPが胃粘膜でAIDの発現を誘導して遺伝子変異を誘導することが明らかとなった。さらにColitic cancerについては、潰瘍性大腸炎における種々のサイトカインがAIDの発現を増強して遺伝子変異を導入し、発癌に寄与していると考えられた。

Research Products

• [Journal Article] A novel mouse model of hepatocarcinogenesis triggered by AID causing deleterious p53 mutations (2009)
  • Author(s): Takai A, Toyoshima T, Uemura M, Kitawaki Y, Marusawa H, Hiai H, Yamada S, Okazaki I, Honjo T, Chiba T, Kinoshita K
  • Journal Title: Oncogene 28 Pages: 469-478(53)
• [Journal Article] Small intestine Peyer's patches are major induction sites of the Helicobacter-induced host immune responses (2008)
  • Author(s): Watanabe N, Kiriya K, Chiba T
  • Journal Title: Gastroenterology 134 Pages: 642-643
• [Journal Article] Activation-induced cytidine deaminase links bile duct inflammation to human cholangiocarcinoma (2008)
  • Author(s): Komori J, Marusawa H, Machimoto T, Endo Y, Kinoshita K, Kou T, Haga H, Ikai I, Uemoto S, Chiba T
  • Journal Title: Hepatology 47 Pages: 888-896
• [Journal Article] REG I α Protein Mediates an Anti-apoptotic Effect of STAT3 Signaling in Gastric Cancer Cells (2008)
  • Author(s): Sekikawa A, Fukui H, Fujii S, Ichikawa K, Tomita S, Imura J, Chiba T, Fujimori T
  • Journal Title: Carcinogenesis 29 Pages: 76-83
• [Journal Article] Coiled-coil domain containing 85B suppresses the β-catenin activity in a p53-dependent manner (2008)
  • Author(s): Iwai A, Hijikata M, Hishiki T, Isono O, Chiba T, Shimotohno K
  • Journal Title: Oncogene 27 Pages: 1520-1526
• [Journal Article] Fatal autoimmune hepatitis induced by concurrent loss of naturally arising regulatory T cells and PD-1-mediated signaling (2008)
  • Author(s): Kido M, Watanabe N, Okazaki T, Akamatsu T, Saga K, Nishio A, Tanaka J, Honjo T, Chiba T
  • Journal Title: Gastroenterology 135 Pages: 1333-1343
• [Journal Article] Activation-induced cytidine deaminase links between inflammation to colitis-associated colorectal cancers (2008)
  • Author(s): Endo Y, Marusawa H, Kou T, Nakase H, Fujii S, Fujimori T, Kinoshita K, Honjo T, Chiba T
  • Journal Title: Gastroenterology 135 Pages: 889-898
• [Journal Article] Organ-specific profiles of genetic changes in cancers caused by activation-induced cytidine deaminase expression (2008)
  • Author(s): Morisawa T, Marusawa H, Ueda Y, Iwai A, Okazaki IM, Honjo T, Chiba T
  • Journal Title: Int J Cancer 123 Pages: 2735-40
• [Journal Article] Mechanism for gastric cancer development by Helicobacter pylori ifection (2008)
  • Author(s): Chiba T, Marusawa H, Seno H, Watanabe N
  • Journal Title: J Gastroenterol Hepatol 23 Pages: 1175-1181
• [Journal Article] Helicobacter pylori immunology and vaccine (2008)
  • Author(s): Vorobjova T, Watanabe T, Chiba T
  • Journal Title: Helicobacter 13(Suppl 1) Pages: 18-22
• [Journal Article] Expression of the REG IV gene in ulcerative colitis (2007)
  • Author(s): Nanakin A, Fukui H, Fujii S, Sekikawa A, Kanda N, Hisatsune H, Seno H, Konda Y, Fujimori T, Chiba T.
  • Journal Title: Lab Invest 87 Pages: 304-314
• [Journal Article] Growth arrest-specific gene 6 and Axl signaling enhances gastric cancer cell survival via Akt pathway (2007)
  • Author(s): Sawabu T, Seno H, Kawashima T, Fukuda A, Uenoyama Y, Kawada M, Kanda N, Sekikawa A, Fukui H, Yanagita M, Yoshibayashi H, Satoh S, Sakai Y, Nakano T, Chiba T.
  • Journal Title: Mol Carcinogenesis 46 Pages: 155-164
• [Journal Article] Expression of activation-induced cytidine deaminase in human hepatocytes during hepatocarcinogenesis (2007)
  • Author(s): Kou T, Marusawa H, Kinoshita K, Endo Y, Okazaki IM, Ueda Y, Kodama Y, Haga H, Ikai I, Chiba T
  • Journal Title: Int J Cancer 120 Pages: 469-476
• [Journal Article] Essential role of Peyer's patches in the development of Helicobacter-induced gastritis (2007)
  • Author(s): Kiriya K, Watanabe N, Nishio A, Okazaki K, Kido M, Saga K, Tanaka J, Akamatsu T, Ohashi S, Asada M, Fukui T, Chiba T
  • Journal Title: Int Immunol 19 Pages: 435-446
• [Journal Article] Glycosylation and palmitoylation of Wnt-3a are coupled to produce an active form of Wnt-3a (2007)
  • Author(s): Komekado H, Yamamoto H, Chiba T, Kikuchi A
  • Journal Title: Genes Cells 12 Pages: 521-534
• [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 IM, Honjo T, Chiba T
  • Journal Title: Nat Med 13 Pages: 470-476
• [Journal Article] Matrix metalloproteinase-7 triggers the matricrine action of insulin-like growth factor binding protein 2 in the extracellular matrix (2007)
  • Author(s): Miyamoto S, Nakamura M, Yano K, Ishii G, Hasebe T, Endoh Y, Sangai T, Maeda H, Shi-Chuang Z, Chiba T, Ochiai A
  • Journal Title: Cancer Sci 98 Pages: 685-691
• [Journal Article] Strategies for improving outcomes for gastric cancer (2007)
  • Author(s): Chiba T, Aoi T
  • Journal Title: (Editorials)J Gastroenterol Hepatol 22 Pages: 965-967
• [Journal Article] Immunoglobulin VH gene analysis in primary gastric MALT lymphoma (2007)
  • Author(s): Sakuma H, Nakamura T, Uemura N, Chiba T, Sugiyama T, Asaka M, Akamatsu T, Ueda R, Eimoto T, Goto H, Nakamura S, Inagaki H
  • Journal Title: Modern Pathol 20 Pages: 460-466
• [Journal Article] Expression of human activation-induced cytidine deaminase in human hepatocytes via NF-kB signaling (2007)
  • Author(s): Endo Y, Marusawa H, Kinoshita K, Morisawa T, Sakurai T, Okazaki IM, Watashi K, Shimotono K, Honjo T, Chiba T
  • Journal Title: Oncogene 26 Pages: 5587-5595
• [Journal Article] Novel IL4 and IL1RN variations associated with non-cardia gastric cancer in Japan : Comprehensive analysis of 207 polymorphisms of 11 cytokines (2007)
  • Author(s): Seno H, Satoh K, Tsuji S, Shiratsuchi T, Harada Y, Hamajima N, Sugano K, Kawano S, Chiba T
  • Journal Title: J Gastroenterol Hepatol 22 Pages: 729-737
• [Journal Article] Chromosomal instability by β-catenin/TCF trascription in APC or β-catenin mutant cells (2007)
  • Author(s): Aoki K, Aoki M, Sugai M, Harada N, Miyoshi H, Tsukamoto T, Mizoshita T, Tatematsu M, Seno H, Chiba T, Oshima M, Hsieh C-L, Taketo MM
  • Journal Title: Oncogene 26 Pages: 3511-3520
• [Journal Article] Cross-Primed CD8(+) Cytotoxic T cells Induce Severe Helicobacter-associated Gastritis in the Absence of CD4(+) T cells (2007)
  • Author(s): Fukui T, Nishio A, Okazaki K, Kasahara K, Saga K, Tanaka J, Uza N, Ueno S, Kido M, Ohashi S, Asada M, Nakase H, Watanabe N, Chiba T
  • Journal Title: Helicobacter 12 Pages: 486-497
• [Journal Article] Gastric mucosal hyperplasia via up-regulation of gastrin induced by persistent activation of gastric innate immunity in MHC class II-deficient mice (2006)
  • Author(s): Fukui T, Nishio A, Okazaki K, Uza N, Ueno S, Kido M, Inoue S, Kitamura H, Kiriya K, Ohashi S, Asada M, Tamaki H, Matsuura M, Kawasaki K, Suzuki K, Uchida K, Fukui H, Nakase H, Watanabe N, Chiba T
  • Journal Title: Gut 55 Pages: 607-615
• [Journal Article] Involvement of cyclooxygenase-2 in gastric mucosal hypertrophy in gastrin transgenic mice (2006)
  • Author(s): Kanda N, Seno H, Kawada M, Sawabu T, Uenoyama T, Nakajima T, Konda Y, Fukui H, Takeuchi T, Chiba T
  • Journal Title: Am J Physiol Gastrointest Liver Physiol 290 Pages: G519-527
• [Journal Article] Risk of subsequent development of gastric cancer in patients with previous gastric epithelial neoplasia (2006)
  • Author(s): Aoi T, Marusawa H, Sato T, Chiba T, Maruyama M
  • Journal Title: Gut 55 Pages: 588-589
• [Journal Article] Hypoxia induced by benign intestinal epithelial cells is associated with cyclooxygenase-2 expression in stromal cells through AP-1-dependent pathway (2006)
  • Author(s): Uenoyama Y, Seno H, Fukuda A, Sekikawa A, Nanakin A, Sawabu T, Kawada M, Kanda N, Suzuki K, Yada N, Fukui H, Chiba T
  • Journal Title: Oncogene 25 Pages: 3277-3285
• [Journal Article] Anti-viral protein APOBEC3G is induced by interferon-alpha stimulation in human hepatocytes (2006)
  • Author(s): Tanaka Y, Marusawa H, Seno H, Matsumoto Y, Ueda Y, Kodama Y, Endo Y, Yamauchi J, Matsumoto T, Takaori-Kondo A, Ikai I, Chiba T
  • Journal Title: Biochem Biophys Res Commun 341 Pages: 314-319
• [Journal Article] Expression of APOBEC2 is transcriptionally regulated by NF-κB in human hepatocytes (2006)
  • Author(s): Matsumoto T, Marusawa H, Endo Y, Ueda Y, Matsumoto Y, Chiba T
  • Journal Title: FEBS Lett 580 Pages: 731-735
• [Journal Article] Host factors are important in determining clinical outcomes of Helicobacter pylori infection (2006)
  • Author(s): Chiba T, Seno H, Marusawa H, Wakatsuki Y, Okazaki K
  • Journal Title: J Gastroenterol 41 Pages: 1-9
• [Journal Article] Signal tranducers of transcription 3 activation is involved in nuclear accumulation of β-catenin in colorectal cancer (2006)
  • Author(s): Kawada M, Seno H, Uenoyama Y, Sawabu T, Kanda N, Fukui H, Shimahara Y, Chiba T
  • Journal Title: Cancer Res 66 Pages: 2913-2917
• [Journal Article] Rapid development of diffuse large B-cell lymphoma after successful eradication of Helicobacter pylori for gastric MALT lymphoma (2006)
  • Author(s): Iwano M, Watanabe N, Matsushima Y, Seno H, Oki K, Sakurai T, Inagaki H, Okazaki K, Chiba T
  • Journal Title: Am J Gastroenterol 101(12) Pages: 2878-2883
• [Journal Article] Loss of function of the candidate tumor suppressor prox1 by RNA mutation in human cancer cells (2006)
  • Author(s): Takahashi M, Yoshimoto T, Shimoda M, Kono T, Koizumi M, Yazumi S, Shimada Y, Doi R, Chiba T, Kubo H
  • Journal Title: Neoplasia 8 Pages: 1003-10
• [Presentation] H. Pylori infection induces gene mutations in gastric epithelial cells via induction of AID (2009)
  • Author(s): 千葉勉、松本裕子、丸澤宏之
  • Organizer: 第82回日本細菌学会総会・シンポジウム
  • Place of Presentation: 名古屋
  • Year and Date: 2009-09-13
• [Presentation] Helicobacter pylori感染によるAID発現を介したヒトゲノム異常生成の分子機構 (2009)
  • Author(s): 丸澤宏之、松本裕子、千葉勉
  • Organizer: 第94回日本消化器病学会総会
  • Place of Presentation: 福岡
  • Year and Date: 2009-05-10
• [Presentation] 遺伝子編集酵素AIDを用いた新しい肝発癌マウスモデルの作成 (2008)
  • Author(s): 高井淳、丸澤宏之、日合弘、千葉勉、木下和生
  • Organizer: 第67回日本癌学会学術総会
  • Place of Presentation: 名古屋
  • Year and Date: 2008-10-28
• [Presentation] Mechanism of H.pylori-induced Gene Mutation in Gastric Carcinogenesis (2008)
  • Author(s): T Chibatric
  • Organizer: AACR Symposium Chemical and Biological Aspects of Inflammation and Cancer
  • Place of Presentation: Oahu Hawaii(USA)
  • Year and Date: 2008-10-15
• [Presentation] Helicobacter pylori infection induces gene mutations in gastric epithelial cells via induction of activation-induced cytidine deaminase(AID) (2008)
  • Author(s): Y Matsumoto, H Marusawa, Y Endo, T Chiba
  • Organizer: 8th International Workshop on Pathogenesis and Host Response in Helicobacter Infections
  • Place of Presentation: Helsinki(Denmark)
  • Year and Date: 2008-07-04
• [Presentation] Helicobacter pylori感染によるAID発現を介した遺伝子変異生成からの胃発癌機構 (2008)
  • Author(s): 千葉勉
  • Organizer: 第12回腸内細菌学会・シンポジウム
  • Place of Presentation: 東京
  • Year and Date: 2008-06-12
• [Presentation] The AID-transgenic mouse : a model for inflammation-associated carcinogenesis in digestive organs (2007)
  • Author(s): H Marusawa, Y Endo, T Chiba
  • Organizer: 66th Annual Meeting of the Japanese Cancer Association
  • Place of Presentation: 横浜
  • Year and Date: 2007-10-03
• [Presentation] Etopic expression of activation-induced cytidine deaminase in ulcerative colitis-associated colorectal cancers (2007)
  • Author(s): T Kou, H Marusawa, Y Endo, H Nakase, S Fujii, K Kinoshita, T Fujimori, T Honjo, T Chiba
  • Organizer: Digestive Disease Week andthe 108th Annual Meeting of the American Gastroenterological Association Institute
  • Place of Presentation: Washington DC(USA)
  • Year and Date: 2007-05-22
• [Presentation] High expression of activation induced cytidine deaminase in human bile duct epithelium during cholangiocarcinogenesis (2007)
  • Author(s): J Komori, H Marusawa, T Machimoto, Y Endo, K Kinoshita, T Kou, H Haga, I Ikai, S Uemoto, T Honjo, T Chiba
  • Organizer: Digestive Disease Week and the 108th Annual Meeting of the American Gastroenterological Association Institute
  • Place of Presentation: Washington DC(USA)
  • Year and Date: 2007-05-20
• [Presentation] Aberrant Expression of Activation-Induced Cytidine Deaminase(AID) and Hepatocarcinogenesis (2006)
  • Author(s): T Kou, H Marusawa, K Kinoshita, I-M Okazaki, Y Ueda, Y Kodama, Y Endo, H Haga, I Ikai, T Chiba
  • Organizer: Digestive Disease Week and the 107th Annual Meeting of the American Gastroenterological Association Institute
  • Place of Presentation: Los Angeles(USA)
  • Year and Date: 2006-05-22
• [Presentation] Anti-Hepatitis B Viral Protein Apobec3g Is Induced By IFN-α Stimulation in Human Hepatocytes (2006)
  • Author(s): Y Tanaka, H Marusawa, Y Matsumoto, Y Ueda, Y Endo, A Takaori-Kondo, I Ikai, T Chiba
  • Organizer: Digestive Disease Week and the 107th Annual Meeting of the American Gastroenterological Association Institute
  • Place of Presentation: Los Angeles(USA)
  • Year and Date: 2006-05-22