State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Department of Gastroenterology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
Liver Int. 2021 Aug;41(8):1956-1968. doi: 10.1111/liv.14892. Epub 2021 Apr 19.
Liver fibrosis is pathologically important in the liver cirrhosis progression. The epithelial-mesenchymal transition (EMT) is crucial for organ fibrosis. Macrophage-stimulating protein (MSP) and its receptor tyrosine kinase, RON, promote cellular EMT. However, their role in liver fibrosis is unclear. Here, we clarify the biological profile, potential mechanisms and therapeutic targets of the MSP-RON pathway in liver fibrosis.
Macrophage-stimulating protein expression and its correlation with clinicopathological characteristics of cirrhosis were evaluated in 57 clinical cases and a control group. The effect of MSP-RON pathway in liver fibrosis was determined in vitro and in vivo. The therapeutic effects of MSP or RON inhibition on liver fibrosis were evaluated in a mouse liver fibrosis model.
Macrophage-stimulating protein is upregulated in liver cirrhosis, which was associated with poor patient prognosis. The MSP-RON pathway promoted hepatocytes EMT. MSP-RON-induced EMT depends on the transforming growth factor beta (TGF-β) pathway and is regulated by TGF-β inhibitors. In animal models, an MSP blocking antibody and a small molecule inhibitor of RON, BMS-777607, both inhibited liver fibrosis progression.
Our study revealed that MSP is an important biomarker in liver cirrhosis progression and can be used to prognose patients. The MSP-RON pathway promotes the EMT of hepatocytes and the progress of fibrosis via a TGF-β related pathway. Consequently, we identified a new treatment strategy for liver cirrhosis through targeted inhibition of MSP/RON. This research increases the understanding of EMT-modulated liver fibrosis and provides new insights into biomarkers and therapeutic targets of liver fibrosis.
肝纤维化在肝硬化进展中具有重要的病理学意义。上皮-间充质转化（EMT）对于器官纤维化至关重要。巨噬细胞刺激蛋白（MSP）及其受体酪氨酸激酶 RON 促进细胞 EMT。然而，它们在肝纤维化中的作用尚不清楚。在这里，我们阐明了 MSP-RON 通路在肝纤维化中的生物学特征、潜在机制和治疗靶点。
评估了 57 例临床病例和对照组中 MSP 表达及其与肝硬化临床病理特征的相关性。在体外和体内研究了 MSP-RON 通路在肝纤维化中的作用。在小鼠肝纤维化模型中评估了 MSP 或 RON 抑制对肝纤维化的治疗效果。
巨噬细胞刺激蛋白在肝硬化中上调，与患者预后不良相关。MSP-RON 通路促进肝细胞 EMT。MSP-RON 诱导的 EMT 依赖于转化生长因子-β（TGF-β）途径，并受 TGF-β 抑制剂的调节。在动物模型中，MSP 阻断抗体和 RON 的小分子抑制剂 BMS-777607 均抑制肝纤维化进展。
我们的研究表明 MSP 是肝硬化进展的重要生物标志物，可用于预测患者的预后。MSP-RON 通路通过 TGF-β 相关途径促进肝细胞 EMT 和纤维化的进展。因此，我们通过靶向抑制 MSP/RON 确定了一种治疗肝硬化的新策略。这项研究增加了对 EMT 调节的肝纤维化的理解，并为肝纤维化的生物标志物和治疗靶点提供了新的见解。
