Epigenetic Regulation Implicates Hypoxia-resistance of Hepatoma Stem Cell Population.
| Project/Area Number |
15590662
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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 | Nagasaki University |
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Principal Investigator |
OHTSURU Akira Nagasaki University, Hospital of Medicine and Dentistry, Associate professor, 医学部・歯学部附属病院, 助教授 (00233198)
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| Co-Investigator(Kenkyū-buntansha) |
NAKAO Kazuhiko Nagasaki University, Health Care Center, Associate Professor, 保健管理センター, 助教授 (00264218)
YANASHITA Shunichi Nagasaki University, Graduate School of Biomedical Sciences, Professor, 大学院・医歯薬学総合研究科, 教授 (30200679)
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| Project Period (FY) |
2003 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥3,400,000 (Direct Cost: ¥3,400,000)
Fiscal Year 2004: ¥1,200,000 (Direct Cost: ¥1,200,000)
Fiscal Year 2003: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | hepatoma / targeting / gene therapy / stem cell / STI571 / NF-kB / 肝細胞がん |
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| Research Abstract |
Terminal growth arrest(TGA) as well as apoptosis plays important role in elimination of dongenic populations after various therapy for hepatoma. We have shown previously that STI571(Gleevec), a selective tyrosine kinase inhibitor, retarded the growth of anaplastic thyroid cancer(ATC) cell lines in vitro and in vivo through selective inhibition of c-Abl tyrosine kinase activity. In the present study, we investigated the ability of Gleevec to modulate the in vitro and in vivo hypoxia response of hepatoma cells. Cell growth assay, colony formation assay and xenograft models were used to quantify Gleevec hypoxiasensitizing effect for hepatoma cell lines HuH7 and HepG2. FACS, Western Blotting and histochemistry techniques were applied to study mechanisms radiation response after Gleevec exposure. Clonogenic analysis demonstrated that Gleevec reduced cell survival after hypoxia stress. Gleevec combined with radiation produced increase in the tumor growth inhibition when compared to treatment with either modality alone in mice bearing ATC xenografts. We investigated several potential mechanisms that may contribute to the enhanced radiation and/or hypoxia responses. Gleevec promoted p21cip 1 accumulation in irradiated ATC cells. Gleevec suppressed radiation-induced c-ABL activation in ARO cells and displayed the induction of terminal growth arrest. Antitumor activity of Gleevec appears to be due to the proliferative growth inhibition associated with the terminal growth arrest associated with senescence. Our study suggest that hepatoma stem cell population is hypoxia resistant and c-Abl suppression is critical for treatment of highly malignant hepatomas.
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Report
(3 results)
Research Products
(19 results)
