炎症から消化器癌の発癌にいたる機序の解明

2008 年度 研究成果報告書

• 研究課題/領域番号: 18209027
• 研究種目: 基盤研究(A)
• 配分区分: 補助金
• 応募区分: 一般
• 研究分野: 消化器内科学
• 研究機関: 京都大学
• 研究代表者: 千葉 勉 京都大学, 医学研究科, 教授 (30188487)
• 連携研究者: 渡部 則彦 京都大学, 医学研究科, 准教授 (50419446)
• 研究期間 (年度): 2006 – 2008
• キーワード: AID / 炎症 / 発癌 / 遺伝子変異 / H. pylori / REG蛋白

研究概要

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。

研究成果

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