Analysis of Esophageal cancer development and Therapy of Esophageal cancer (Analysis of COX-2 activation mechanism by Bile reflux in Esophageal cancer cells)
| Project/Area Number |
17591392
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Digestive surgery
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| Research Institution | Tazuke Kofukai Medical Research Institute (2006)
Kyoto University (2005) |
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Principal Investigator |
KAGANOI Junichi Tazuke Kofukai Medical Research Institute, 3rd laboratory, chief researcher, 医学研究所・第5研究部, 研究員 (60378619)
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| Co-Investigator(Kenkyū-buntansha) |
WATANABE Go Kyoto University, Medical Research Institute, Assistant professor, 医学研究科, 講師 (50293866)
SHIMADA Yutaka Kyoto University, Medical Research Institute, Assistant professor, 医学研究科, 講師 (30216072)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,800,000 (Direct Cost: ¥1,800,000)
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| Keywords | Esophageal Cancer / Cancer Depelopment / Gastroesophageal Reflux Disease / COX-2 / Cytokines / EGFR / IFN_γ / STAT1 / 食道内胆汁逆流現象 |
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| Research Abstract |
Bile acids are known to promote the growth of gastrointestinal cancer. However, the underlying mechanism remains unclear. We examined whether bile acids induce tumor growth via the cyclooxygenase (COX)-2 angiogenic pathway. In vitro, esophageal squamous cell carcinoma (ESCC) cells and esophageal adenocarcinoma cells were studied. Production of prostaglandin E2 (PGE2) and vascular endothelial growth factor (VEGF) in response to treatment with chenodeoxycholic acid (CDCA) was assessed by enzyme-linked immunosorbent assay (ELISA). COX-2 protein and VEGF protein were measured by immunoblot analysis, and COX-2 activity was measured by ELISA. In vivo, CDCA was administered to ESCC cell-bearing mice. Tumor tissues were analyzed immunohistochemically, and microvessel density was evaluated. Clinically, 134 patients with ESCC who underwent esophagectomy were studied. In vitro, CDCA induced the production of PGE2 and VEGF in dose-and time-dependent manners, and these effects were attenuated by a selective COX-2 inhibitor, mitogen-activated protein kinases inhibitor, or epidermal growth factor receptor inhibitor. CDCA-induced COX-2 in the cell lysate increased the secretion of VEGF into the culture medium. In vivo, CDCA markedly enhanced tumor growth and increased vascularization. Clinically, patients whose tumors expressed both COX-2 and VEGF had poor outcomes. Our results suggest that bile acids, important constituents of duodenal fluid, stimulate the development of human esophageal cancer by promoting angiogenesis via the COX-2 pathway.
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Report
(3 results)
Research Products
(2 results)
