COX-2 and mPGES on proliferation-differentiation cycle of epithelial cells
| Project/Area Number |
15390127
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | KYOTO UNIVERSITY |
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Principal Investigator |
OSHIMA Masanobu Kyoto University, Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (40324610)
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| 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)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| 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)
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| Keywords | gastric 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 |
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| 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.
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Report
(3 results)
Research Products
(28 results)
