Effectofheat-shockprotein-90(HSP90)inhibitiononhumanhepatocytesandonliverregeneration.docVIP

中国普外基础与临床杂志 普外科学新知栏目 电子版供稿单 题目 Title Resources Surgery.2010 May;147(5):704-12. 原文发布日期 Date 16/12/2009 供稿内容 Contents 由于热休克蛋白-90（ HSP90）已经用于治疗癌症引起了人们极大的兴趣，但靶向治疗在肝修复和再生中的影响也引起了人们的忧虑。Hackl C等人便研究在小鼠模型中HSP90抑制剂对肝再生的影响。他们的研究主要是在试管内的人体肝细胞中探究HSP90抑制剂对激活信号中间体，VEGF的表达，HGF的影响。在小鼠肝切除模型和急性四氯化碳（ CCL（ 4 ））引起的肝损害模型中测定了HSP90抑制剂对肝再生和修复的影响。最后他们发现靶向HSP90的抑制作用有效减少了PHHs中Akt、Ert和STAT3结构的磷酸化。相反，HSP90的抑制作用显著增加了VEGF和HGF两种mRNA的表达，且 HSP90的抑制不损害肝部分切除术后或者发生在CCl（4）中毒性肝损伤后的肝再生。。所以HSP90抑制剂不会对体内的肝再生和修复的多因素过程造成负面影响。 原文题目 Title Effect of heat-shock protein-90 (HSP90) inhibition on human hepatocytes and on liver regeneration in experimental models 原文摘要 Abstract (全文请以PDF格式打包发送) BACKGROUND: Targeting heat shock protein 90 (HSP90) has gained great interest for cancer therapy. However, in view of novel multimodality therapy approaches for treating hepatic metastases, concerns have raised regarding the impact of targeted therapies on liver regeneration and repair. In this study, we investigated the impact of HSP90 inhibition on liver regeneration in murine models. METHODS: Effects of HSP90 inhibition on the activation of signaling intermediates, expression of vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF) were investigated in primary human hepatocytes (PHHs) in vitro. Effects of HSP90 inhibition on liver regeneration and repair were determined in a murine hepatectomy model and in a model with acute carbon tetrachloride (CCl(4))-induced liver damage. RESULTS: Inhibition of HSP90 effectively diminished the constitutive phosphorylation of Akt, Erk, and STAT3 in PHHs. Conversely, inhibition of HSP90 significantly increased the expression of both VEGF and HGF mRNA, and induced HSP70 protein in PHH cultures in vitro. In vivo, HSP90 inhibition significantly upregulated constitutive VEGF mRNA and HSP70 in murine livers and did not impair liver re-growth after 70% hepatectomy. Furthermore, BrdUrd-staining and histological quan