| Project/Area Number |
17591471
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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 |
Thoracic surgery
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| Research Institution | HIROSHIMA UNIVERSITY |
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Principal Investigator |
MIYATA Yoshihiro Hiroshima University, Graduate School of Biomedical Sciences, Research Associate, 大学院医歯薬学総合研究科, 助手 (50397965)
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| Co-Investigator(Kenkyū-buntansha) |
ASAHARA Toshimasa Hiroshima University, Hospital, Professor, 病院・教授 (70175850)
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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 |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2006: ¥1,700,000 (Direct Cost: ¥1,700,000)
Fiscal Year 2005: ¥1,700,000 (Direct Cost: ¥1,700,000)
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| Keywords | heparanase / hepatocellular carcinoma / tumor recurrence / Heparanase |
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| Research Abstract |
If the rat hepatocellular carcinoma (HCC) tissue was implanted into another syngeneic rat liver, all animals died of pulmonary metastasis with a mean survival period of 116.7 days. If the HCC bearing liver was replaced by the allogeneic liver graft with tacrolimus administration, survival of rats did not significantly prolonged due to tumor recurrence. Tacrolimus plus ROCK inhibitor-treatment, however, significantly prolonged the survival of liver grafted rats with a mean survival period 303.1 days. Rats that had not been treated with the ROCK inhibitor showed multiple metastatic nodules in the lungs, whereas no metastatic pulmonary nodules were found in rats treated with the ROCK inhibitor. This is a noble model system that mimics the tumor recurrence and metastasis in the immune-sufficient animals. We are now investigating whether heparanase induced HCC cells can alter the tumor recurrence status.
We have shown that tacrolimus activated Rho/ROCK signal pathway to enhance cell migration of rat HCC cells and the ROCK inhibitor reduced tacrolimus-induced migration of rat hepatocellular carcinoma cells in vitro. Tacrolimus-induced cell migration was associated with phosphorylation state of MLC, a downstream effector of Rho/ROCK signaling. The activity of phosphorylated MLC was significantly suppressed by the addition of ROCK inhibitor. On the other hand, tacrolimus does not increase the proliferation of hepatocellular carcinoma cells by MTT assays. We also developed the heparanase induced cell lines that produced heparanase in vitro. We investigated whether heparanase induced HCC cells increased the capacity of migration. Our findings indicate that tacrolimus activates the Rho/ROCK signal pathway to stimulate cell motility of rat HCC cells and enhances the invasiveness of rat HCC cells. Further, we have also shown that the ROCK inhibitor suppressed tumor recurrence after liver transplantation in a rat HCC model.
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