缺氧诱导的炎症在促进肝癌侵袭及转移中占有关键地位，是肿瘤研究热点之一。细胞外组蛋白是一种新型炎症介质，在维持肝脏炎症反应中发挥重要作用，但是细胞外组蛋白在肝癌中的病理作用尚未阐明。申请者前期工作发现：细胞外组蛋白可以诱导大量趋化因子的产生及释放，促进肝癌细胞的侵袭及转移。基于此，本项目将首先采用肝癌患者及多种肝癌细胞株为研究对象，应用Western Blot、免疫荧光及ELISA等技术观察缺氧诱导细胞外组蛋白的释放及其在肝癌患者血清和组织中的表达情况；然后采用基因沉默、化学药物阻断等干预手段，体外观察细胞外组蛋白对肝癌细胞增殖、侵袭以及转移的影响以及相关分子机制；最后通过建立两种小鼠肝癌模型，在体内验证细胞外组蛋白在肝癌侵袭、转移中的作用。开展本项目将有望阐明缺氧诱导细胞外组蛋白释放并促进肝癌侵袭及转移的分子机制，进一步丰富肝癌的病理学说，为肝癌的诊治提供新的途径。

Hypoxia-mediated inflammation plays a crucial role in migration and invasion of hepatocellular carcinoma (HCC). Extracellular histone is a novel cancer-related inflammatory mediator although its role in HCC still remains largely unknown. Our previous work demonstrated that extracellular histone induces the production and release of a number of chemokines, which contributes to migration and invasion of HCC cells. These findings suggest that extracellular histone is implicated in the pathology of HCC. In this study, we will observe expression and release of histone in HCC patients as well as hypoxia-induced histone release in HCC cells by Western Blot, ELISA and immunofluorescence. Next, we will define the molecular mechanism of hypoxia-induced extracellular histone release and their effects on proliferation, migration and invasion of HCC cells by RNAi and pharmaceutical inhibitors. Finally, we will investigate the effects of extracellular histone on tumor growth and metastasis in vivo by two different animal models of HCC (subcutaneous tumor transplantation and lung metastasis of HCC via tail vein injection). Collectively, this study will clarify the molecular mechanism of hypoxia-induced extracellular histone release in promoting HCC migration and invasion, and provide evidence for therapeutic intervention targeted histone in the prevention and interruption of HCC metastasis.