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Promotion of liver regeneration and intrahepatic metastasis of hepatocellular carcinoma by Histone acetylation

组蛋白乙酰化促进肝细胞癌肝再生及肝内转移

基本信息

批准号：
14370392
负责人：
SHIMADA Mitsuo
金额：
$ 8.96万
依托单位：
The Universuty of Tokushima (2004)Kyushu University (2002-2003)
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
2002
资助国家：
日本
起止时间：
2002 至 2004
项目状态：
已结题

项目摘要

【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 … More 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

[目的]探讨组蛋白乙酰化对肝细胞癌（HCC）侵袭、转移及分化的影响。此外，我们评估了组蛋白乙酰化在肝再生过程中的作用。[方法与结果]（1）组蛋白去乙酰化酶1（HDAC 1）在肝癌中的作用：HDAC 1的高表达与肝癌的增殖和侵袭性有关，HDAC 1高表达者预后差。（2）HDAC抑制剂对肝再生的影响：给予HDAC抑制剂曲古抑菌素A（TSA）后，大鼠肝切除70%，肝再生速度加快（BrdU标记指数和有丝分裂指数升高）。肝细胞特异性基因的表达在再生早期没有下调。（3）抑制HDAC对肝癌转移、分化及肝再生的影响：TSA可降低HDAC的表达，抑制人肝癌细胞的增殖。 ...更多信息 CC细胞系（HepG 2和HuH 7）。TSA对肝癌细胞系有诱导分化作用。cDNA微阵列显示TSA处理的细胞中一些肝细胞特异性基因表达上调。TSA的管理，然后是70%的肝切除术和脾内肝癌细胞的管理减少了大鼠肝转移的数量。（4）HDAC反义诱导的作用：HDAC 1反义诱导人肝癌细胞株HDAC 1表达降低，细胞增殖受到抑制。此外，HDAC 1反义的诱导加速了白蛋白的合成（HCC细胞系的分化）。（5）HDAC抑制和COX-Ⅱ：γ-亚油酸（GLA）降低HCC细胞系的细胞活力，改变与细胞周期相关的基因表达。此外，GLA降低COX-Ⅱ表达，改变肝组织脂肪酸组成。在大鼠中，GLA加速70%肝切除术后的肝再生，并抑制皮下肿瘤模型中的肿瘤生长。[结论]抑制组蛋白去乙酰化可促进肝切除后肝再生，并促进再生过程中肝细胞的特异性功能。抑制HDAC可促进肝癌细胞的分化，抑制肝癌细胞的转移。这些结果表明，控制组蛋白乙酰化应该是肝再生和HCC的新靶点。少