Crosstalk between CagA and inflammation in H. pylori-related gastric carcinogenesis.

• Project/Area Number: 24659365
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Single-year Grants
• Research Field: Gastroenterology
• Research Institution: Osaka University
• Principal Investigator: TSUJII Masahiko 大阪大学, 医学(系)研究科(研究院), 准教授 (40303937)
• Co-Investigator(Kenkyū-buntansha): TAKEHARA Tetsuo 大阪大学, 大学院医学系研究科, 教授 (70335355) ; IIJIMA Hideki 大阪大学, 大学院医学系研究科, 講師 (90444520) ; NISHIDA Tsutomu 大阪大学, 大学院医学系研究科, 助教 (20467575)
• Project Period (FY): 2012-04-01 – 2014-03-31
• Project Status: Completed (Fiscal Year 2013)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2013: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000); Fiscal Year 2012: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 胃癌 / ヘリコバクターピロリ / CagA / 腸上皮化生 / 胃炎 / let-7 / 炎症

Research Abstract

In in vitro experiments, CagA significantly attenuated let-7 expression leading to Ras pathway activation. CagA enhanced c-myc, DNA methyltransferase 3B (DNMT3B) and Enhancer of Zeste homologue 2 (EZH2) expression and attenuated miR-26a and miR-101 expression, which resulted in the attenuation of let-7 expression by histone and DNA methylation. Experiments performed in CagA transgenic mice revealed that c-myc, EZH2 and DNMT3B expression were enhanced and let-7 expression was attenuated to induce Ras oncoprotein expression in the stomach, with no associated inflammation. It is concluded that H pylori CagA induces aberrant epigenetic silencing of let-7 expression, leading to Ras upregulation.

Research Products

• [Journal Article] Clinical features of post-polypectomy bleeding associated with heparin bridge therapy. (2014)
  • Author(s): Inoue T, Nishida T, Maekawa A, Tsujii Y, Akasaka T, Kato M, Hayashi Y, Yamamoto S, Kondo J, Yamada T, Shinzaki S, Iijima H, Tsujii M, Takehara T.
  • Journal Title: Dig Endosc. Volume: 26 Issue: 2 Pages: 243-249
  • DOI: 10.1111/den.12123
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• [Journal Article] Atypical duodenal ulcer and invagination caused by a large pedunculated duodenal Brunner's gland hamartoma. (2014)
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  • Journal Title: Gastrointest Endosc. Volume: 79 Issue: 4 Pages: 679-680
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• [Journal Article] Concomitant use of romiplostim and chemotherapy for advanced rectal cancer associated with idiopathic thrombocytopenic purpura (2014)
  • Author(s): Yamada M, Shinzaki S, Nishida T, Yamada T, Fujinaga T, Yakushijin T, Tatsumi T, Iijima H, Hiramatsu N, Tsujii M, Takehara T.
  • Journal Title: 日本消化器病学会雑誌 Volume: 111 Pages: 521-528
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• [Journal Article] Amelioration of Small Bowel Injury by Switching from Nonselective Nonsteroidal Anti-Inflammatory Drugs to Celecoxib in Rheumatoid Arthritis Patients: A Pilot Study (2013)
  • Author(s): Inoue, T., Iijima, H., Arimitsu, J., Hagihara, K., Kawai, S., Shiraishi, E., Hiyama, S., Mukai, A., Shinzaki, S., Nishida, T., Ogata, A., Tsujii, M., Takehara, T.
  • Journal Title: Digestion Volume: 89 Issue: 2 Pages: 124-132
  • DOI: 10.1159/000357229
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• [Journal Article] Esophageal pyogenic granuloma developed after short-term fol low-up. (2013)
  • Author(s): Saito Y, Nishida T, Kato M, et al.
  • Journal Title: Dis Esophagus Volume: 26(Epub 2012 May 9.) Issue: 3 Pages: 343-344
  • DOI: 10.1111/j.1442-2050.2012.01351.x
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• [Journal Article] Acute suppurative pancreatic ductitis associated with pancreatic duct obstruction. (2013)
  • Author(s): Fujinaga T, Nishida T, Miyazaki M, Shigekawa M, Ikezawa K, Iwahashi K, Inoue T, Yamada T, Ezaki H, Shinzaki S, Yakushijin T, Iijima H, Tsujii M, Takehara T.
  • Journal Title: Endoscopy Volume: 45 Issue: S 02 Pages: 135-135
  • DOI: 10.1055/s-0032-1326450
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• [Journal Article] Choroidal and cutaneous metastasis from gastric adenocmcinoma. (2013)
  • Author(s): Kawai S, Nishida T, Hayashi Y, et al.
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  • DOI: 10.3748/wjg.v19.i9.1485
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• [Journal Article] Lectin-based immunoassay for aberrant IgG glycosylation as the biomarker for Crohn's disease. (2013)
  • Author(s): Shinzaki S, 他13名, Naka T, Plevy S E, Takehara T, Miyoshi E.
  • Journal Title: Inflamm Bowel Dis. Volume: 19（2） Issue: 2 Pages: 321-31
  • DOI: 10.1097/mib.0b013e318280eade
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• [Journal Article] Evaluation of endoscopic ultrasound image quality is necessary in endosonographic assessment of early gastric cancer invasion depth (2013)
  • Author(s): Yamamoto S, Nishida T, Iijima H, Tsujii M, Takehara T.
  • Journal Title: Gastroenterol Res Pract Pages: 164530-164530
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/?term=endosonographic+assessment+of+yamamoto+s
• [Journal Article] CagA mediates epigenetic regulation to attenuate let-7 expression in Helicobacter pylori-related carcinogenesis. (2013)
  • Author(s): Hayashi Y, Tsujii M, Wang J, Kondo J, Akasaka T, Jin Y, Li W, Nakamura T, Nishida T, Iijima H, Tsuji S, Kawano S, Hayashi N, Takehara T.
  • Journal Title: GUT Volume: 62 Issue: 11 Pages: 1536-1546
  • DOI: 10.1136/gutjnl-2011-301625
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• [Journal Article] Scheduled endoscopic surveillance controls secondary cancer after curative endoscopic resection for early gastric cancer : a multicentre retrospective cohort study by Osaka University ESD study group (2013)
  • Author(s): Kato M, Nshida T, Iijima H, Tsujii M, Takehara T.
  • Journal Title: Gut Volume: 62 Issue: 10 Pages: 1425-1432
  • DOI: 10.1136/gutjnl-2011-301647
• [Journal Article] Mucosa-associated lymphoid tissue (MALT) lymphoma of the esophagus. (2013)
  • Author(s): Tsujii Y, Nishida T, Kato M, et al.
  • Journal Title: Dis Esophagus. 2013 Apr : 26(3) : 349-50. Volume: 26.(Epub 2012 Aug 7.) Issue: 3 Pages: 349-350
  • DOI: 10.1111/j.1442-2050.2012.01387.x
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• [Journal Article] Managing hepatitis B virus carriers with systemic chemotherapy or biologic therapy in the outpatient clinic. (2013)
  • Author(s): Nishida T
  • Journal Title: Hepatol Res. Volume: 43 Issue: 4 Pages: 339-346
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• [Journal Article] Post-transplant lymphoproliferative disorder of the ileum diagnosed by double-balloon enteroscopy. (2013)
  • Author(s): Tawara S, Shinzaki S, Nishida T, Kato M, Hiyama S, Inoue T, Iijima H, Tsujii M, Takehara T.
  • Journal Title: Endoscopy. Volume: 45 Issue: S 02 Pages: 380-381
  • DOI: 10.1055/s-0033-1344828
  • Peer Reviewed
• [Journal Article] Gastric ESD under Heparin Replacement at High-Risk Patients of Thromboembolism Is Technically Feasible but Has a High Risk of Delayed Bleeding: Osaka University ESD Study Group. (2013)
  • Author(s): Yoshio T, Nishida T, Kawai N, Yuguchi K, Yamada T, Yabuta T, Komori M, Yamaguchi S, Kitamura S, Iijima H, Tsutsui S, Michida T, Mita E, Tsujii M, Takehara T.
  • Journal Title: Gastroenterol Res Pract. Volume: 2013 Pages: 365830-365830
  • DOI: 10.1155/2013/365830
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• [Journal Article] Narrow Band Imaging with Magnifying Endoscopy for Peyer's Patches in Patients with Inflammatory Bowel Disease (2013)
  • Author(s): Hiyama, S., Iijima, H., Shinzaki, S., Mukai, A., Inoue, T., Shiraishi, E., Kawai, S., Yamada, T., Nishida, T., Tsujii, M., Takehara, T.
  • Journal Title: Digestion Volume: 87 Issue: 4 Pages: 269-80
  • DOI: 10.1159/000349953
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• [Journal Article] Hemobilia into a metallic biliary stent due to pseudoaneurysm: a case report (2013)
  • Author(s): Morishita N, Nishida T, Hayashi Y, Iwahashi K, Ikezawa K, Shigekawa M, Shinzaki S, Yamada T, Kakita N, Ezaki H, Miyazaki M, Yakushijin T, Tatsumi T, Iijima H, Kiso S, Hiramatsu N, Tsujii M, Osuga K, Terashima K, Takehara T.
  • Journal Title: 日本消化器病学会雑誌 Volume: 110 Pages: 2127-2135
  • NAID: 130003383333
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• [Journal Article] Cyclooxygenase, cancer stem cells and DNA methylation play important roles in colorectal carcinogenesis (2013)
  • Author(s): Tsujii, M.
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• [Journal Article] Functional Network between Bone and Organs. Gastrointestinal diseases and bone (2013)
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• [Journal Article] Epste in-Barr virus-associated early gastric cancer presenting as an elevated lesion. (2012)
  • Author(s): Yamamoto S, Nishida T, Tsujii M, et al.
  • Journal Title: Endoscopy Volume: 44(Epub 2012 May 23.) Issue: S 02 Pages: 222-223
  • DOI: 10.1055/s-0032-1309353
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• [Journal Article] Altered oligosaccharide structures contribute to ameliorate murine colitis defective in beta 1,4 galactosyltransferase I. (2012)
  • Author(s): Shinzaki S, Miyoshi E, et al.
  • Journal Title: Gastroenterology Volume: 142(5) Issue: 5 Pages: 1172-82
  • DOI: 10.1053/j.gastro.2012.02.008
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• [Journal Article] Protective role of adiponec t in against ethanol-induced gastric injury in mice. (2012)
  • Author(s): Yamamoto S, ffatabe K, Araki H, et al.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Volume: 302(Epub 2012 Feb 9) Issue: 8 Pages: G773-G780
  • DOI: 10.1152/ajpgi.00324.2011
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• [Journal Article] Deficiency of N-acetylgalactosamine in O-linked oligosaccharides of IgA is a novel biologic marker for inflammatory bowel diseases. (2012)
  • Author(s): InoueT, Miyoshi E, et al.
  • Journal Title: IBD Journal Volume: 18(9) Issue: 9 Pages: 1723-34
  • DOI: 10.1002/ibd.22876
  • Peer Reviewed
• [Journal Article] Evaluation of endoscopic ultrasound image quality is necessary in endosonographic assessment of early gastric cancer invasion depth (2012)
  • Author(s): Yamamoto, S. Nishida, T. Kato, M. et al.
  • Journal Title: Gastroenterol Res Pract Volume: 2012 Pages: 194530-194530
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• [Journal Article] Biomarkers in the diagnosis and therapy of inflammatory bowel diseases (2012)
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• [Journal Article] Regulation of anergy-related ubiquitin E3 ligase, GRAIL, in murine models of colitis and patients with Crohn's disease
  • Author(s): Mukai A, Iijima H, H, Nishida T, Tsujii M, Takehara T.
  • Journal Title: J Gastroenterol Volume: (in press)
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/24356810
• [Journal Article] Peyer's Patches Play a Protective Role in Nonsteroidal Anti-inflammatory Drug-induced Enteropathy in Mice
  • Author(s): Hiyama S, Iijima H, Tsujii M, Takehara T.
  • Journal Title: Inflamm Bowel Dis Volume: (in press)
  • URL: http://www.ncbi.nlm.nih.gov/pubmed/24651581
• [Presentation] Cyclooxygenase-2の癌幹細胞バイオロジー、DNA異常メチル化に及ぼす影響.ワークショップ;消化管がん分子病態診断学の進歩 (2012)
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  • Organizer: 第8回日本消化管学会
  • Place of Presentation: 仙台
• [Presentation] ESD後の適切なフォローアップ方法～多発胃癌に対するサーベイランスの観点から～ESDフォーラム; Where is our destination? (2012)
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  • Organizer: 第8回日本消化管学会
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• [Presentation] ヘパリン置換療法下での大腸内視鏡的粘膜切除後出血の検討.シンポジウム;抗凝固薬・抗血小板薬服用患者の内視鏡診療を検証する (2012)
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  • Organizer: 第83回日本消化器内視鏡学会総会
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• [Presentation] Long-term outcomes of ESD for patients with early gastric cancer and liver cirrhosis : a multicenter study by Osaka University ESD Study Group (2012)
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  • Organizer: 2012 Digestive Disease Week and the Annual Meeting of the American Society for Gastrointestinal Endoscopy
  • Place of Presentation: San Diego, USA
• [Presentation] Narrow band imaging with magnifying endoscopy for Peyer's patches in patients with inflammatory bowel disease (2012)
  • Author(s): Hiyama S, Nishida T, Tsujii M, Takehara T.
  • Organizer: 2012 Digestive Disease Week and the Annual Meeting of the American Society for Gastrointestinal Endoscopy
  • Place of Presentation: San Diego, USA
• [Presentation] Role of DNA methylation on epithelial mesenchymal transition (EMT)-like phenotype of colon cancer cells (2012)
  • Author(s): Kondo J, Nishida T, Watabe K, Tsujii M, Takehara T.
  • Organizer: 2012 Digestive Disease Week and the Annual Meeting of the American Society for Gastrointestinal Endoscopy
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• [Presentation] Clinical features of late bleeding associated with heparin replacement after endoscopic resection for colorectal neoplasms (2012)
  • Author(s): Inoue T, Iijima H, Tsujii M, Takehara T.
  • Organizer: 2012 Digestive Disease Week and the Annual Meeting of the American Society for Gastrointestinal Endoscopy
  • Place of Presentation: San Diego, USA
• [Presentation] 胃癌発生と腸上皮化生H.pylori起因性胃発癌におけるCagAと腸上皮化生の役割 (2012)
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