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COX-2 and mPGES on proliferation-differentiation cycle of epithelial cells

Research Project

Project/Area Number 15390127
Research Category

Grant-in-Aid for Scientific Research (B)

Allocation TypeSingle-year Grants
Section一般
Research Field Experimental pathology
Research InstitutionKYOTO UNIVERSITY

Principal Investigator

OSHIMA Masanobu  Kyoto University, Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (40324610)

Co-Investigator(Kenkyū-buntansha) OSHIMA Hiroko  Kyoto University, Graduate School of Medicine, Assistant Professor(Tokunin), 医学研究科, 研究員(科学技術振興)(常勤形態) (80362515)
Project Period (FY) 2003 – 2004
Project Status Completed (Fiscal Year 2004)
Budget Amount *help
¥15,400,000 (Direct Cost: ¥15,400,000)
Fiscal Year 2004: ¥6,700,000 (Direct Cost: ¥6,700,000)
Fiscal Year 2003: ¥8,700,000 (Direct Cost: ¥8,700,000)
Keywordsgastric cancer / inflammation / COX-2 / mPGES-1 / macrophage / TNF-α / prostaglandin / mouse model / Toll-like receptor / トランスジェニックマウス / PGE_2 / ヘリコバクター
Research Abstract

Cyclooxygenase-2(COX-2), a rate-limiting enzyme for prostanoid biosynthesis, plays an important role in tumor development. Microsomal prostaglandin E synthase (mPGES)-1, an inducible enzyme for PGE_2 synthesis, is functionally coupled with COX-2, and upregulated in some tumors. Expression of both COX-2 and mPGES-1 is up-regulated in the gastric cancer tissues as well as colon cancer. To investigate the role of PGE_2 in gastric tumorigenesis, we constructed transgenic mice (K19-C2mE mice) expressing COX-2 and mPGES-1 simultaneously in the glandular stomach. The transgenic mice developed hyperplastic tumors with heavy macrophage infiltrations. Although gastric bacterial counts in the transgenic mice were within the normal range, treatment with antibiotics significantly suppressed activation of the macrophages and tumorous hyperplasia. Importantly, the antibiotics-treatment did not affect the macrophage accumulation. Notably, treatment of the gastric epithelial cells with bacterial LPS induced TNF-α through Toll-like receptor4. These results indicate that an increased PGE_2 enhances macrophage accumulation, and that gastric flora stimulates epithelial cells to activate macrophages, resulting in hyperplastic tumor development. To investigate furher the role of proinflammatory cytokines, we introduced respective knockout mutations of TNF-α and IL-1β receptor into the K19-C2mE mice. Disruption of TNF-α suppressed gastric tumor formation significantly, while IL-1β knockout did not affect the gastric phenotypes. Accordingly, these results demonstrate that TNF-α-associated inflammation is responsible for hyperplastic gastric tumorigenesis. It is possible that inhibition of TNF-α prevents inflammation-associated gastric tumorigenesis.

Report

(3 results)
  • 2004 Annual Research Report   Final Research Report Summary
  • 2003 Annual Research Report
  • Research Products

    (28 results)

All 2005 2004 2003 Other

All Journal Article (25 results) Publications (3 results)

  • [Journal Article] A targeted mutation of Nkd1 impairs mouse spermatogenesis.2005

    • Author(s)
      Li, Q., et al.
    • Journal Title

      Journal of Biological Chemistry 280

      Pages: 2831-2839

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] ROCK-I regulates closure of the eyelids and ventral body wall by inducing assembly of actomyosin bundles.2005

    • Author(s)
      Shimizu, Y., et al.
    • Journal Title

      Journal of Cell Biology 168

      Pages: 941-953

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hypergravity induces expression of cyclooxygenase-2 in the heart vessels.2005

    • Author(s)
      Oshima, M., et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 330

      Pages: 928-933

    • NAID

      120000809421

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hypergravity induces expression of cyclooxygenase-2 in the heart vessels.2005

    • Author(s)
      Oshima, M. et al.
    • Journal Title

      Biochem.Biophys.Res.Commun. 330(3)

      Pages: 928-933

    • NAID

      120000809421

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] ROCK-I regulates closure of the eyelids and ventral body wall by inducing assembly of actomyosin bundles.2005

    • Author(s)
      Shimizu, Y et al.
    • Journal Title

      Journal of Cell Biology 168(6)

      Pages: 941-953

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] A targeted mutation of Nkd1 impairs mouse spermatogenesis.2005

    • Author(s)
      Li, Q, et al.
    • Journal Title

      Journal of Biological Chemistry 280(4)

      Pages: 2831-2839

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hypergravity induces expression of cyclooxygenase-2 in the heart vessels.2005

    • Author(s)
      Oshima, M., et al.
    • Journal Title

      Biochemical and Biophysical Research Communications 330

      Pages: 928-933

    • NAID

      120000809421

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Hepatocarcinogenesis in mice with β-catenin and Ha-ras gene mutations2004

    • Author(s)
      Harada, N., et al.
    • Journal Title

      Cancer Research 64

      Pages: 48-54

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Simultaneous expression of COX-2 and mPGES-1 in mouse gastrointestina hamartomas.2004

    • Author(s)
      Takeda, H., et al.
    • Journal Title

      British Journal of Cancer 90

      Pages: 701-704

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice.2004

    • Author(s)
      Oshima, H., et al.
    • Journal Title

      EMBO Journal 23

      Pages: 1669-1678

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes.2004

    • Author(s)
      Kawada, K., et al.
    • Journal Title

      Cancer Research 64

      Pages: 4010-4017

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Annual Research Report 2004 Final Research Report Summary
  • [Journal Article] Development of spontaneous tumors and intestinal lesions in Fhit knockout mice.2004

    • Author(s)
      Fujishita, T., et al.
    • Journal Title

      British Journal of Cancer 91

      Pages: 1571-1574

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Development of spontaneous tumors and intestinal lesions in Fhit gene knockout mice.2004

    • Author(s)
      Fujishita, T et al.
    • Journal Title

      British Journal of Cancer 91(8)

      Pages: 1571-1574

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Pivotal role of CXCR3 in melanoma cell metastasis to lymph nodes.2004

    • Author(s)
      Kawada, K et al.
    • Journal Title

      Cancer Research 64(11)

      Pages: 4010-4017

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice.2004

    • Author(s)
      Oshima, H et al.
    • Journal Title

      EMBO Journal 23(7)

      Pages: 1669-1678

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Simultaneous expression of COX-2 and mPGES-1 in mouse gastrointestinal hamartomas.2004

    • Author(s)
      Takeda, H et al.
    • Journal Title

      British Journal of Cancer 90(3)

      Pages: 701-704

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hepatocarcinogenesis in mice with β-catenin and Ha-ras gene mutations.2004

    • Author(s)
      Harada, N., et al.
    • Journal Title

      Cancer Research 64(1)

      Pages: 48-54

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Hyperplastic gastric tumors induced by activated macrophages in COX-2/mPGES-1 transgenic mice.2004

    • Author(s)
      Oshima, K, et al.
    • Journal Title

      EMBO Journal 23

      Pages: 1669-1678

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Development of spontaneous tumors and intestinal lesions in Fhit knockout mice.2004

    • Author(s)
      Fujishite, T., et al.
    • Journal Title

      British Journal of Cancer 91

      Pages: 1571-1574

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Cooperation of cyclooxygenase 1 and cyclooxygenase 2 in intestinal polyposis.2003

    • Author(s)
      Takeda, H., et al.
    • Journal Title

      Cancer Research 63

      Pages: 4872-4877

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Colonic polyposis caused by mTOR-mediated chromosomal instability iApc^<Δ716> Cdx2^<+/-> compound mutant mice.2003

    • Author(s)
      Aoki, K., et al.
    • Journal Title

      Nature Genetics 35

      Pages: 323-330

    • Description
      「研究成果報告書概要(和文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc+/Delta7l6 Cdx2+/- compound mutant mice.2003

    • Author(s)
      Aoki K, et al.
    • Journal Title

      Nature Genetics 35(4)

      Pages: 323-330

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Cooperation of cyclooxygenase 1 and cyclooxygenase 2 in intestinal polyposis.2003

    • Author(s)
      Takeda, H et al.
    • Journal Title

      Cancer Research 63(16)

      Pages: 4872-4877

    • Description
      「研究成果報告書概要(欧文)」より
    • Related Report
      2004 Final Research Report Summary
  • [Journal Article] Cooperation of cyclooxygenase 1 and cyclooxygenase 2 in intestinalpolyposis.2003

    • Author(s)
      Takeda, H., et al.
    • Journal Title

      Cancer Research 63

      Pages: 4872-4877

    • Related Report
      2004 Annual Research Report
  • [Journal Article] Colonic polyposis caused by mTOR-mediated chromosomal instability in Apc^<Δ716> Cdx2^<+/-> compound mutant mice.2003

    • Author(s)
      Aoki, K., et al.
    • Journal Title

      Nature Genetics 35

      Pages: 323-330

    • Related Report
      2004 Annual Research Report
  • [Publications] Oshima, H., et al.: "Hyperplastic gastric tumors induced by activated macrophages in COX-2 / mPGES-1 transgenic mice"EMBO J.. 23・7(in press). (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Takeda, H., et al.: "Simultaneous expression of COX-2 and mPGES-1 in mouse gastrointestinal hamartomas"Br.J.Cancer. 90・3. 701-704 (2004)

    • Related Report
      2003 Annual Research Report
  • [Publications] Takeda, H., et al.: "Cooperation of cyclooxygenase 1 and cyclooxygenase 2 in intestinal polyposis"Cancer Res.. 63・16. 4872-4877 (2003)

    • Related Report
      2003 Annual Research Report

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Published: 2003-04-01   Modified: 2016-04-21  

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