| Project/Area Number |
14370392
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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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 Universuty of Tokushima (2004)
Kyushu University (2002-2003) |
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Principal Investigator |
SHIMADA Mitsuo The University of Tokushima, Institute of Health Biosciences, Professor, 大学院・ヘルスバイオサイエンス研究部, 教授 (10216070)
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| Co-Investigator(Kenkyū-buntansha) |
FUJII Masahiko Tokusihima University, Hospital, Assistant Professor, 大学院・医学部・歯学部附属病院, 助手 (20380040)
田中 真二 九州大学, 大学病院, 講師 (30253420)
調 憲 九州大学, 大学病院, 講師 (70264025)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥14,000,000 (Direct Cost: ¥14,000,000)
Fiscal Year 2004: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2003: ¥3,700,000 (Direct Cost: ¥3,700,000)
Fiscal Year 2002: ¥9,000,000 (Direct Cost: ¥9,000,000)
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| Keywords | Histone acetylation / liver regeneration / hepatocellular carcinoma / differentiation induction / intrahepatic metastasis / gamma linoleic acid / COX-2 / 肝特異的遺伝子 / 肝切除後肝内転移モデル |
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| Research Abstract |
【Aim】
The aim of this study was to clarify the effect of histone acetylation on invasion, metastasis as well as differentiation of hepatocellular carcinoma (HCC). In addition, we evaluated the role of histone acetylation during liver regeneration.
【Methods and results】
(1)The role of histone deacetylase 1 (HDAC1) expression in HCC : High expression of HDAC1 was correlated with proliferation and invasion of HCC, and patients with increased expression of HDAC1 exhibited a poor prognosis.
(2)The effect of HDAC inhibition on liver regeneration : Administration of HDAC inhibitor, Trichostatin A (TSA), followed by 70% of hepatectomy in rats, accelerated liver generation (higher values of BrdU labeling index and mitosis index). The expression of hepatocyte-specific genes was not down-regulated in the early phase regeneration.
(3)Effect of HDAC inhibition on metastasis and differentiation of HCC, and liver regeneration : TSA redeuced the expression of HDAC and inhibited the proliferation of human H
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CC cell lines (HepG2 and HuH7). Inversely, TSA induced the differentiation of HCC cell lines. cDNA microarray revealed that some hepatocyte-specific genes were upregulated in TSA-treated cells. Administration of TSA followed by 70% of hepatectomy and intrasplenic administration of hepatoma cells reduced the number of liver metastases in rats.
(4)Effect of HDAC antisense induction : Induction of HDAC1 antisense to human HCC cell line decreased the expression of HDAC1 and inhibited cell proliferation. In addition, induction of HDAC1 antisense accelerated albumin synthesis (differentiation of HCC cell lines).
(5)HDAC inhibition and COX-II : Gamma linoleic acid (GLA) decreased cell viability of HCC cell lines and altered the gene expression associated with cell cycle. In addition, GLA decreased COX-II-expression and altered the constitution of fatty acid in the liver tissues. In rats, GLA accelerated liver regeneration after 70% hepatectomy, and inhibited tumor growth in the subcutaneous tumor model.
【Conclusion】
Inhibition of histone deacetylation accelerated liver regeneration after hepatectomy and hepatocyte-specific function during regeneration. In addition, the inhibition of HDAC promoted and differentiation of HCC cell lines and inhibited metastasis of HCC cells. Those results suggest that control of histone acetylation should be a new target for liver regeneration and HCC. Less
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