| Project/Area Number |
16590632
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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 |
|---|
| Research Field |
Gastroenterology
|
|---|
| Research Institution | Keio University |
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Principal Investigator |
HIGUCHI Hajime Keio University, Department of Medicine, Instructor, 医学部, 助手 (20306682)
|
|---|
| Project Period (FY) |
2004 – 2005
|
| Project Status |
Completed (Fiscal Year 2005)
|
| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2005: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2004: ¥2,300,000 (Direct Cost: ¥2,300,000)
|
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| Keywords | interferon / hepatocellular carcinoma / cyclooxygenase-2 / TRAIL / Death Receptor / apoptosis / caspase / interferon |
|---|
| Research Abstract |
We identified that cyclooxygenase (COX)-2 gene is markedly upregulated in hepatocellular carcinoma (HCC) cells in response to interferon-beta treatment. Anti-apoptotic function of COX-2 is crucial in HCC cell apoptosis resistance. Apoptosis was identified by 4',6-diamidino-2-phenylindole dihydrochloride (DAPI) and fluorescent staining. IFN-β could up-regulate the expression of TRAIL, while NS-398 increased the expression of TRAIL receptors (especially of death receptor 5). Subsequently, activation of caspase-8 and caspase-3 was observed following the treatment with NS-398 and IFN-β in HepG2 cells. Blockade of TRAIL abrogated cell death induced by a combination of NS-398 and IFN-β in both HepG2 and HuH7 cells. Co-treatment with prostaglandin E2 partially abrogated NS-398+IFN-β-induced cell death in HuH7 cells, but not in HepG2 cells. Furthermore, in vivo experiment showed the combined regimen with NS-398 and IFN-β could reduce the growth of xenotransplated HCCs in nude mice. In conclusion, NS-398 is sufficient to overcome IFN resistance in hepatoma cells through the TRAIL/TRAIL receptor and COX-2 signaling pathway, therefore, the combination would appear to be an new therapeutic regimen for HCC.
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