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

【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脏再生中的作用。【方法与结果】(1)组蛋白去乙酰化酶1 （HDAC1）表达在HCC中的作用：HDAC1的高表达与HCC的增殖和侵袭相关，HDAC1表达升高的患者预后较差。(2) HDAC抑制对肝脏再生的影响：给予HDAC抑制剂曲古他汀A (Trichostatin A， TSA)，然后在大鼠肝切除70%后，加速肝脏生成（BrdU标记指数和有丝分裂指数较高）。肝细胞特异性基因的表达在再生早期不下调。(3)抑制HDAC对肝癌转移、分化及肝再生的影响：TSA降低HDAC的表达，抑制人肝癌细胞株HepG2和HuH7的增殖。相反，TSA诱导HCC细胞系分化。cDNA微阵列显示，一些肝细胞特异性基因在tsa处理的细胞中上调。在70%的肝切除术和脾内给药后给予TSA可减少大鼠肝转移的数量。(4) HDAC反义诱导的作用：HDAC反义诱导人HCC细胞系后，HDAC1的表达降低，细胞增殖受到抑制。此外，诱导HDAC1反义蛋白加速白蛋白合成（HCC细胞系分化）。(5)HDAC抑制和COX-II: γ亚油酸（GLA）降低HCC细胞系细胞活力，改变细胞周期相关基因表达。此外，GLA还能降低cox - ii的表达，改变肝组织中脂肪酸的构成。在大鼠肝切除70%后，GLA可促进肝脏再生，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术后肝脏再生和再生过程中的肝细胞特异性功能。此外，抑制HDAC可促进肝癌细胞系分化，抑制肝癌细胞转移。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

【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