硫酸酯酶活性片段阻断肝纤维化演进及癌变的作用机制研究

Hepatic fibrosis is an important procedure of chronic liver disease from cirrhosis to carcinogenesis. Many cytokines promote hepatic mesenchymal cells to transform into myofibroblasts and secrete extracellular matrix (ECM), then accelerate the progression of hepatic fibrosis. The sulfation of cell surface heparan sulfate proteoglycans (HSPG) is a step necessary to activate the growth factor receptor signaling pathway. The human sulfatase 1 (hSulf-1) can desulfate HSPG and negatively modulates the growth factor signaling. Our previous studies found that the TGF-β1-activated AKT/ERK signaling pathways can stimulate hepatic stellate cells (HSC) to secrete ECM, and accelerate the progression of hepatic fibrosis. the functional fragment of hSulf-1 (N-Sulf) has the same activity as full-length hSulf-1 and can desulfate HSPG to negatively modulate the growth factor signaling, finally impede the progression of hepatic fibrosis. This project will observe the influences of N-Sulf on TGF-β1-mediated downstream signaling pathways, investigate the efficacy of N-Sulf in inhibiting HSC activation and hepatic fibrosis and decreasing the probability of carcinogenesis in HBV-transgenic mouse hepatic fibrosis model and DEN-induced rat hepatic fibrosis and carcinogenesis models. The project will establish a novel target strategy for effectively impeding hepatic fibrosis and prevent carcinogenesis.

肝纤维化是慢性肝病向肝癌发展的重要环节，多种生长因子促肝间质细胞转化为肌成纤维细胞，分泌细胞外基质ECM，诱发肝纤维化。细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）的硫酸化是生长因子信号通路激活的必要步骤，而硫酸酯酶hSulf-1可使HSPG脱硫酸化，抑制生长因子信号途径的激活。我们前期研究发现，由TGF-β1启动的AKT/ERK等信号通路激活促进肝星状细胞（HSC）活化并分泌ECM，启动肝纤维化发生。hSulf-1活性片段（N-Sulf）同样具有HSPG脱硫酸化功能，抑制多种生长因子受体激酶活性，阻断肝纤维化演进。本研究拟观察N-Sulf对HSC细胞TGF-β1等下游信号通路的影响,在HSC诱导的HBV转基因小鼠肝纤维化模型和DEN诱导的大鼠肝纤维化癌变模型的不同病程阶段进行干预，了解N-Sulf抑制HSC活化和肝纤维化、降低癌变几率的功效，从而建立有效肝纤维化及癌变的干预性生物治疗新策略。

肝纤维化是慢性肝病向肝癌发展的重要环节，多种生长因子促肝间质细胞转化为肌成纤维细胞，分泌细胞外基质ECM，诱发肝纤维化。细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）的硫酸化是生长因子信号通路激活的必要步骤，而硫酸酯酶hSulf-1可使HSPG脱硫酸化，抑制生长因子信号途径的激活。我们前期研究发现，由TGF-β1启动的AKT/ERK等信号通路激活促进肝星状细胞（HSC）活化并分泌ECM，启动肝纤维化发生。hSulf-1活性片段（N-Sulf）同样具有HSPG脱硫酸化功能，抑制多种生长因子受体激酶活性，阻断肝纤维化演进。本研究拟观察N-Sulf对HSC细胞TGF-β1等下游信号通路的影响,在HSC诱导的HBV转基因小鼠肝纤维化模型和DEN诱导的大鼠肝纤维化癌变模型的不同病程阶段进行干预，了解N-Sulf抑制HSC活化和肝纤维化、降低癌变几率的功效，从而建立有效肝纤维化及癌变的干预性生物治疗新策略。.按照考核指标要求，已完成所有研究任务，包括：(1) 完成肝纤维化演进及癌变的可能分子机制，确立TGF-β1等多种生长因子激活的信号通路在HSC、MSC细胞活化增殖及其诱发的肝纤维化演进中的作用；(2) 完成在HBV诱导的小鼠肝纤维化、DEN诱导的大鼠肝纤维化癌变模型中，证实hSulf-1的全长基因表达产物及其酶活性功能片段N-Sulf可通过阻断生长因子配体与细胞表面特异性受体结合，全面抑制多种生长因子信号通路的受体激酶活性，发挥抗纤维化的生物功能；(3) 完成发表论文任务。