Mechanism for genomic instability during inflammation-associated carcinogenesis

2012 Fiscal Year Final Research Report

• Project/Area Number: 21229009
• Research Category: Grant-in-Aid for Scientific Research (S)
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Kyoto University
• Principal Investigator: CHIBA Tsutomu 京都大学, 医学研究科, 教授 (30188487)
• Co-Investigator(Kenkyū-buntansha): KINOSHITA Yoshikazu 島根大学, 医学部, 教授 (30243306) ; MARUSAWA Hiroyuki 京都大学, 医学研究科, 講師 (80324630) ; WATANABE Tomohiro 京都大学, 医学研究科, 准教授 (40444468) ; UEDA Yoshihide 京都大学, 医学研究科, 講師 (90378662)
• Project Period (FY): 2009 – 2012
• Keywords: 上部消化管学 / 消化器発癌

Research Abstract

Many cancers arise with the background of inflammation, and cancerdevelopment is associated with accumulation of various gene aberrations.Activation-induced cytidine deaminase (AID) is exclusively expressed in B lymphocytesand plays important roles in induction of class-switch recombination (CSR) and somatichypermutation (SHM) of the immunoglobulin (Ig) genes, resulting in diversification ofIg genes in physiological condition. We found in this study that AID is ectopicallyexpressed in epithelial cells during inflammation, and is involved ininflammation-associated cancer development by inducing various gene aberrationsincluding gene mutations and deletions and duplications in epithelial cells.

Research Products

• [Journal Article] Nardilysin and ADAM proteasespromote gastric cancer cell growth byactivating intrinsic cytokine signalingvia enhanced ectodomain shedding of TNFα (2012)
  • Author(s): Kanda K, Komekado H, Sawabu T, Ishizu S,Nakanishi U, Nakatsuji M, Akitake-Kawano R, Ohono M, Hiraoka Y, Kawada M,Kawada K, Sakai Y, Matsumoto K,Kunichika M, Kimura T, Seno H, Nishi E,Chiba T
  • Journal Title: EMBO Mol Med Volume: 4 Pages: 396-411
  • DOI: doi:10.1002/emmm.201200216
  • Peer Reviewed
• [Journal Article] Excessive activity of apolipoproteinB mRNA editing enzyme catalyticpolypeptide 2 (APOBEC2) contiributes toliver and lung tumorigenesis. (2012)
  • Author(s): Okuyama S, Marusawa H, Matsumoto T, UedaY, Matsumoto Y, Endo Y, Takai A, ChibaT.
  • Journal Title: Int Jcancer Volume: 130 Pages: 1294-1301
  • DOI: doi:10.1002/ijc.26114
  • Peer Reviewed
• [Journal Article] The role of Hes genes in intestinaldevelopment, homeostasis and tumorformation (2012)
  • Author(s): Ueo T, Imayoshi T, Kobayashi T, OhtsukaT, Seno H, Nakae H, Chiba T, Kageyama R
  • Journal Title: Development Volume: 139 Pages: 1071-1082
  • DOI: doi:10.1242/dev.069070
  • Peer Reviewed
• [Journal Article] Targeting activation-inducedcytidine deaminase prevents coloncancer development despite persistentcolonic inflammation (2012)
  • Author(s): Takai A, Marusawa H, Minaki Y, WatanabeT, Nakase H, Kinoshita K, Tsujimoto G,Chiba T.
  • Journal Title: Oncogene Volume: 31 Pages: 1733-1742
  • DOI: doi:10.1038/onc.2011.352
  • Peer Reviewed
• [Journal Article] Chitinase3-like 1 promotes macrophagerecruitment and angiogenesis incolorectal cancer (2012)
  • Author(s): Kawada M, Seno H, Kanda K, Nakanishi Y,Akitake R, Komekado H, Kawada K, SakaiY, Mizoguchi E, Chiba T
  • Journal Title: Oncogene Volume: 31 Pages: 3111-3123
  • DOI: doi:10.1038/onc.2011.498
  • Peer Reviewed
• [Journal Article] Sensing of commensalorganisms by the intracellular sensorNOD1 mediates experimental pancreatitis (2012)
  • Author(s): Tsuji Y, Watanabe T, Kudo M, Arai H,Strober W, Chiba T
  • Journal Title: Immunity Volume: 37 Pages: 326-338
  • DOI: doi:10.1016/j.immuni.2012.05.024.
  • Peer Reviewed
• [Journal Article] Inflammation-associated cancerdevelopment in digestive organs:Mechanisms and roles for genetic andepigenetic modulation-. (2012)
  • Author(s): Chiba T, Marusawa H, Ushijima T
  • Journal Title: Gastroenterology Volume: 143 Pages: 550-563
  • DOI: doi:/10.1053/j.gastro.2012.07.009
  • Peer Reviewed
• [Journal Article] Molecular mechanism ofcolitis-associated colorectalcarcinogenesis (2012)
  • Author(s): Marusawa H, Endo Y, Takai A, Chiba T
  • Journal Title: Inflamm Regeneration Volume: 32 Pages: 67-71
  • URL: http://dx.doi.org/10.2492/inflammregen.32.067
  • Peer Reviewed
• [Journal Article] Dysregulated generation of follicularhelper T cells in the spleen triggersfatal autoimmune hepatitis in mice (2011)
  • Author(s): Aoki N, Kido M, Iwamoto S, Nishiura H,Maruoka R, Tanaka J, Watanabe T, TanakaY, Okazaki T, Chiba T, Watanabe N.
  • Journal Title: Gastroenterology Volume: 140 Pages: 1322-1333
  • URL: http://dx.doi.org/10.1053/j.gastro.2011.01.002
  • Peer Reviewed
• [Journal Article] Loss of RUNX3 expression by histonedeacetylation is associated withbiliary tract carcinogenesis (2011)
  • Author(s): Shio S, Kodama Y, Ida H, Shiokawa M,Kitamura K, Hatano E, Uemoto S, Chiba T.
  • Journal Title: Cancer Sci Volume: 102 Pages: 776-783
  • DOI: doi:10.1111/j.1349-7006.2011.01848.x
  • Peer Reviewed
• [Journal Article] Acquisition of genetic aberrations byactivation-induced cytidine deaminase(AID) during inflammation-associatedcarcinogenesis (2011)
  • Author(s): Takai A, Marusawa H, Chiba T
  • Journal Title: Cancers Volume: 3 Pages: 2750-2766
  • DOI: doi:10.3390/cancers3022750
  • Peer Reviewed
• [Journal Article] Activation of typeI IFN signaling by NOD1 mediatesmucosal host defense againstHelicobacter pylori infection (2011)
  • Author(s): Watanabe T, Asano N, Kitani A, Fuss IJ,Chiba T, Strober W
  • Journal Title: GutMicrobes Volume: 2 Pages: 61-65
  • URL: http://dx.doi.org/10.4161/gmic.2.1.15162
  • Peer Reviewed
• [Journal Article] Dual roles of CagA protein inHelicobacter pylori-induced chronicgastritis in mice (2011)
  • Author(s): Kido M, Watanabe N, Aoki N, Iwamoto S,Nishiura H, Maruoka R, Ikeda A, Azuma T,Chiba T
  • Journal Title: Biophys Biochem ResCommun Volume: 412 Pages: 266-272
  • URL: http://dx.doi.org/10.1016/j.bbrc.2011.07.081
  • Peer Reviewed
• [Journal Article] Bileacid-induced expression ofactivation-induced cytidine deaminaseduring the development of Barrett'soesophageal adenocarcinoma. (2011)
  • Author(s): Morita S, Matsumoto Y, Okuyama S, Ono K,Kitamura Y, Tomori A, Oyama T, Amano Y,Kinoshita Y, Chiba T, Marusawa H.
  • Journal Title: Carcinogenesis Volume: 32 Pages: 1706-1712
  • DOI: doi:10.1093/carcin/bgr194
  • Peer Reviewed
• [Journal Article] Role ofactivation-induced cytidine deaminasein inflammation-associated cancerdevelopment (2011)
  • Author(s): Marusawa H, Takai A, Chiba T
  • Journal Title: Adv Immunol Volume: 111 Pages: 109-141
  • URL: http://dx.doi.org/10.1016/B978-0-12-385991-4.00003-9
• [Journal Article] COX2 inhibition alters the phenotype of tumor-associated macrophages from M2 toM1 in ApcMin/+ mouse polyps (2011)
  • Author(s): Nakanishi Y, Nakatsuji M, Seno H, IshizuS, Akitake-Kawano R, Kanda K, Ueo T,Komekado H, Kawada M, Minami M, Chiba T
  • Journal Title: Carcinogenesis Volume: 32 Pages: 1333-1339
  • DOI: doi:10.1093/carcin/bgr128.
  • Peer Reviewed
• [Journal Article] DMBT1 is a novel geneinduced by IL-22 in ulcerative colitis (2011)
  • Author(s): Fukui H, Sekikawa A, Tanaka H,Fujimori Y, Katake Y, Fujii S,Ichikawa K, Tomita S, Imura J, ChibaT, Fujimori T
  • Journal Title: Inflamm Bowel Dis Volume: 17 Pages: 1177-1188
  • DOI: doi:10.1002/ibd.21473
  • Peer Reviewed
• [Journal Article] Involvementof activation-induced cytidinedeaminase in the development ofcolitis-associated colorectal cancers (2011)
  • Author(s): Endo Y, Marusawa H, Chiba T
  • Journal Title: J Gastroenterol Volume: 46 (Suppl 1) Pages: 6-10
  • DOI: doi:10.1007/s00535-010-0326-1
  • Peer Reviewed
• [Journal Article] Ligand-specificantibodies to insulin-like growthfactors suppress intestinal polypformation in apc +/- mice (2010)
  • Author(s): Matsunaka T, Miyamoto S, Shitara K,Ochiai A, Chiba T
  • Journal Title: Mol cancerTher Volume: 9 Pages: 419-428
  • DOI: doi:10.1158/1535-7163.MCT-09-0524
  • Peer Reviewed
• [Journal Article] Helicobacterpylori-induced activation-inducedcytidine deaminase expression andcarcinogenesis (2010)
  • Author(s): Marusawa H, Chiba T
  • Journal Title: Curr Opi Immunol Volume: 22 Pages: 442-447
  • DOI: doi:10.1016/j.coi.2010.06.001
• [Journal Article] NOD1contributes to mouse host defenseagainst Helicobacter pylori viainduction of type I IFN and activationof the ISGF3 signaling (2010)
  • Author(s): Watanabe T, Asano N, Fichtner-Feigl S,Gorelick PL, Tsuji Y, Matsumoto Y, ChibaT, Fuss IJ, Kitani A, Strober W
  • Journal Title: J Clin Invest Volume: 120 Pages: 1645-1662
  • DOI: doi:10.1172/JCI39481.
  • Peer Reviewed
• [Journal Article] H.pylori infection -The route frominflammation to cancer. In Sansonetti P,ed, Infection Biology Handbook Series.Bacterial Virulence. Basic principles,models and global approaches (2010)
  • Author(s): Chiba T, Marusawa H, Seno H, Watanabe N
  • Journal Title: Willey-Blackwell Pages: 31-41
• [Journal Article] Up-regulation of activation-inducedcytidine deaminase causes geneticaberrations at the CDKN2b-CDKN2a ingastric cancer (2010)
  • Author(s): Matsumoto Y, Marusawa H, Kinoshita K,Niwa Y, Sakai Y, Chiba T
  • Journal Title: Gastroenterology Volume: 139 Pages: 1984-1994
  • DOI: doi:10.1053/j.gastro.2010.07.010.
  • Peer Reviewed
• [Journal Article] A novelmouse model of hepatocarcinogenesistriggered by AID causing deleteriousp53 mutations (2009)
  • Author(s): Takai A, Toyoshima T, Uemura M, KitawakiY, Marusawa H, Hiai H, Yamada S, OkazakiI, Honjo T, Chiba T, Kinoshita K
  • Journal Title: Oncogene Volume: 28 Pages: 469-478
  • DOI: doi:10.1038/onc.2008.415.
  • Peer Reviewed
• [Journal Article] Attenuation of proteolysis-mediatedcyclin E regulation by alternativelyspliced Parkin in human colorectalcancers (2009)
  • Author(s): Ikeuchi K, Marusawa H, Fujiwara M,Matsumoto Y, Endo Y, Watanabe T, Iwai A,Sakai Y, Takahashi R, Chiba T
  • Journal Title: Int J Cancer Volume: 125 Pages: 2029-2035
  • DOI: doi:10.1002/ijc.24565
  • Peer Reviewed
• [Journal Article] Expression profile of REG familyproteins, REG Iα and REGIV in advancedgastric cancer: Comparison withmucinous phenotype and prognosticmarkers. (2009)
  • Author(s): Yamagishi H, Fukui H, Sekikawa A, KonoT, Fujii S, Ichikawa K, Tomita S, ImuraJ, Hiraishi H, Chiba T, Fujimori T
  • Journal Title: Modern Pathol Volume: 22 Pages: 906-913
  • DOI: doi:10.1038/modpathol.2009.41
  • Peer Reviewed
• [Presentation] Roles of AID inH (2011)
  • Author(s): Tsutomu Chiba
  • Organizer: pylori-induced gastriccarcinogenesis Frontiers in CancerScience 2011
  • Place of Presentation: Singapore.
  • Year and Date: 2011-11-03
• [Presentation] 慢性炎症により誘導されるゲノム異常からの肝癌発生機構 (2011)
  • Author(s): 丸澤宏之
  • Organizer: 第70回日本癌学会学術総会・International sessions
  • Place of Presentation: 名古屋
  • Year and Date: 2011-10-04
• [Presentation] Mechanism forinduction of genetic aberration byHelicobacter pylori (2011)
  • Author(s): Tsutomu Chiba
  • Organizer: XXIVthInternational workshop onHelicobacter and related bacteria inchronic digestive inflammation andgastric cancer・symposium
  • Place of Presentation: Dublin, Ireland
  • Year and Date: 2011-09-13
• [Presentation] Activation of toll-like receeptorsand NOD-like receptors provides amechanism for enhanced IgG4 receptorsin autoimmune. (2011)
  • Author(s): Tomohiro Watanabe, Tsutomu Chiba
  • Organizer: 15th InternationalCongress of Mucosa Immunology
  • Place of Presentation: Paris, France.
  • Year and Date: 2011-07-08
• [Presentation] The role of somaticmutations accumulated in hepaticstem/ progenitor cells in the deveropment of hepatocellular carcinoma (2010)
  • Author(s): Atsushi Takai, Hiroyuki Marusawa Tsutomu Chiba
  • Organizer: The 1st JSGE International TopicConference
  • Place of Presentation: 鎌倉
  • Year and Date: 2010-09-25
• [Presentation] Gastric CancerDevelopment by Helicobacter pyloriInfection - Important Roles ofActivation-induced CytidineDeaminase(AID) in induction of GeneMutations and Genomics Instabilityduring Inflammation-associatedCarcinogenesis (2010)
  • Author(s): Tsutomu Chiba
  • Organizer: Singapore GastricCancer Consortium 3rd AnnualScientific Meeting
  • Place of Presentation: Singapore.
  • Year and Date: 2010-07-15
• [Presentation] Actibation-inducedcytidine deaminase(AID)plays animportant role in induction of genemutations and genomic instabilityduring inflammation-associatedcarcinogenesis (2009)
  • Author(s): Tsutomu Chiba
  • Organizer: The 25th Radiationbiology center internationalsymposium Genomic instability:Mechanism and diseases: session
  • Place of Presentation: 京都
  • Year and Date: 2009-12-01
• [Presentation] A novel mechanism forimflammation - associatedcarcinogenesis - A role for activation-induced cytidine deaminase (AID) inmutation induction-. (2009)
  • Author(s): Tsutomu Chiba
  • Organizer: Scuola didottorato in Scienze della Vita edella Salute Dottorato in Bioscienze,indirizzo Genomica
  • Place of Presentation: Italy
  • Year and Date: 2009-07-21
• [Presentation] Role of AID inH.pylori-induced gasric cancerdevelopment (2009)
  • Author(s): Tsutomu Chiba
  • Organizer: 2009 29th InternationalSymposiumu on cancer Helicobacterpylori and Gastric Cancer
  • Place of Presentation: 札幌
  • Year and Date: 2009-07-13
• [Presentation] Mechanism for gastriccancer development by H.pyloriinfection (2009)
  • Author(s): Tsutomu Chiba
  • Organizer: 6th InternationalConference of Gastroenterology
  • Place of Presentation: Shanghai.
  • Year and Date: 2009-07-03
• [Presentation] H.pylori感染による胃癌発癌機構 (2009)
  • Author(s): 千葉 勉、丸澤宏之、渡部則彦
  • Organizer: 第106回日本内科学会講演会・シンポジウ
  • Place of Presentation: 東京
  • Year and Date: 2009-04-10