2004 Fiscal Year Final Research Report Summary
Molecular mechanisms of the effect of bile acids on colon carcinogenesis via nuclear receptor
| Project/Area Number |
15591410
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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 | The University of Tokushima |
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Principal Investigator |
UMEMOTO Atsushi The University of Tokushima, Department of Oncological and Regenerative Surgery, Associate Professor, 大学院・ヘルスバイオサイエンス研究部, 助教授 (60185072)
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| Co-Investigator(Kenkyū-buntansha) |
HONDA Junko The University of Tokushima, Department of Oncological and Regenerative Surgery, Assistant, 医学部・歯学部附属病院, 助手 (10346611)
HORI Hitoshi The University of Tokushima, Faculty and School of Engineering, Professor, 工学部, 教授 (90119008)
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| Project Period (FY) |
2003 – 2004
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| Keywords | FXR / Bile acid / COX-1 / COX-2 / Colon carcinogenesis |
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| Research Abstract |
The study was conducted to examine the effects of bile acids via bile acid receptor FXR on the gene expression that related to the colon carcinogenesis and the metabolism of bile acid using FXR knock-out mice.
Materials and Methods
Dimethylhydrazine was administered to both FXR FXR -/- C57BL/6N and FXR +/+ wild mice for every 12 weeks, and basal diet, chenodeoxycholic acid (CDCA) diet and ursodeoxycholic acid (UDCA) diet were fed. At 43 weeks, the mRNA expression of COX-1 and COX-2 of the colon were examined. In another experiments, the effects of bile acids on mRNA expression of eleven bile acid-metabolizing enzymes were studied using FXR -/- mice.
Results
The mRNA expressions of COX-1 and COX-2 were increased by knock-out of FXR. The expression of COX-1 was increased by CDCA, but that of COX-2 was not altered in both FXR +/+ and FXR -/- mice. The expressions of COX-1 and COX-2 were increased by UDCA in the FXR +/+ mice, but not in the FXR -/- mice. In both basal diet group and CDCA-administered group, formation of colonic tumor was suppressed by knock-out of FXR, but this was observed only in male mice. The colonic tumor formation in the FXR -/- mice was suppressed by administration of UDCA. The mRNA expressions of Mrp3, Mrp4 and MDR-1a were not altered by bile acids in both FXR +/+ and FXR -/- mice, but were decreased by knock-out of FXR.
Conclusion
FXR affects the expression of COX-1 and COX-2, and UDCA alters the expression of COX-1 and COX-2 via FXR. It was showed that the possibility that CDCA promotes the colonic cancer development through FXR. It was also suggested that the mRNA expressions of Mrp3, Mrp4 and MDR-1a might be always stimulated through FXR by intrinsic bile acids that were present in the colonic lumen.
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Research Products
(1 results)
