| Project/Area Number |
18590733
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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 |
Gastroenterology
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| Research Institution | Shimane University |
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Principal Investigator |
ISHIMURA Norihisa Shimane University, Faculty of Medicine, assistant professor (40346383)
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| Co-Investigator(Kenkyū-buntansha) |
ISHIHARA Shunji Shimane University, Faculty of Medicine, associate professor (80263531)
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| Project Period (FY) |
2006 – 2007
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| Project Status |
Completed (Fiscal Year 2007)
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| Budget Amount *help |
¥3,470,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥270,000)
Fiscal Year 2007: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
Fiscal Year 2006: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | cancer / Cholangiocarcinoma / apoptosis / invasion / TRAIL |
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| Research Abstract |
Tumor necrosis factor related apoptosis inducing ligand (TRAIL) induces apoptosis in various cancer cells but not in normal tissues through TRAIL receptors DR4 and DR5. Although many cancers including cholangiocarcinoma are resistant to TRAIL-mediated apoptosis, the mechanisms remain obscure. Thus our aim was to elucidate the cellular mechanisms by which TRAIL promotes cell migration and/or invasion in human cholangiocarcinoma cells.
Results
1. TRAIL protein was enhanced in cholangiocarcinoma tissues, but not normal tissues. TRAIL receptor protein expression was not enhanced in cholangiocarcinoma. Among the apoptotic related agents, Mc1-1 protein expression was significantly enhanced in cholangiocarcinoma. In cholangiocarcinoma cell lines, TRAIL protein was also enhanced as compare to immortalized cholangiocytes.
2. The differences of promoter sequences in TRAIL between normal and choangiocarcinoma was not detected.
3. TRAIL promoted tumor cell migration and invasion in cholangiocarinoma cells. TRAIL-mediated cell migration and invasion was NF-KB and Mcl-1 dependent. Cholangiocarcinoma cells transfected with TRAIL siRNA could potentially decrease cell migration and invasion. In conclusion, TRAIL potently stimulates tumor cell migration and invasion in cholangiocarcinoma cells and inhibition of Mcl-1 and NF-KB reduces TRAIL-mediated cell migration and invasion. Although TRAIL is being promoted as a promising anticancer drug, TRAIL-mediated invasiveness of apoptosis resistant cancer cells may restrict its use to apoptosis-sensitive tumors. The combination of TRAIL and inhibitors of Mcl-1 and/or NF-KB may be useful for apoptosis resistant cholangiocarcinoma cell
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