Kwon Young-Chan, Sasaki Reina, Meyer Keith, Ray Ranjit
Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA.
Department of Internal Medicine, Saint Louis University, St. Louis, Missouri, USA
J Virol. 2017 Oct 13;91(21). doi: 10.1128/JVI.01235-17. Print 2017 Nov 1.
Endoglin is part of the TGF-β receptor complex and has a crucial role in fibrogenesis and angiogenesis. It is also an important protein for tumor growth, survival, and cancer cell metastasis. In a previous study, we have shown that hepatitis C virus (HCV) infection induces epithelial-mesenchymal transition (EMT) state and cancer stem-like cell (CSC) properties in human hepatocytes. Our array data suggested that endoglin (CD105) mRNA is significantly upregulated in HCV-associated CSCs. In this study, we have observed increased endoglin expression on the cell surface of an HCV core-expressing hepatocellular carcinoma (HepG2) cell line or immortalized human hepatocytes (IHH) and activation of its downstream signaling molecules. The status of phospho-SMAD1/5 and the expression of inhibitor of DNA binding protein 1 (ID1) were upregulated in HCV-infected cells or viral core gene-transfected cells. Additionally, we observed upregulation of endoglin/ID1 mRNA expression in chronic HCV patient liver biopsy samples. CSC generation by HCV core protein was dependent on the endoglin signaling pathway using activin receptor-like kinase 1 (ALK1) Fc blocking peptide and endoglin small interfering RNA (siRNA). Further, follow-up from analysis suggested that the antiapoptosis Bcl2 protein, proliferation-related cyclin D1 protein, and CSC-associated Hes1, Notch1, Nanog, and Sox2 proteins are enhanced during infection or ectopic expression of HCV core protein. Endoglin plays a crucial role in fibrogenesis and angiogenesis and is an important protein for tumor growth, survival, and cancer cell metastasis. Endoglin enhances ALK1-SMAD1/5 signaling in different cell types, leading to increased proliferation and migration responses. We have observed endoglin expression on the HCV core-expressing cell surface of human hepatocyte origin and activation of phospho-SMAD1/5 and ID1 downstream signaling molecules. ID1 protein plays a role in CSC properties, and we found that this pathway is important for antiapoptotic and cell proliferation signaling. Blocking of endoglin-ALK1-SMAD1/5 might be a good candidate for therapy for liver cancer stem cells together with liver cirrhosis.
内皮糖蛋白是转化生长因子-β（TGF-β）受体复合物的一部分，在纤维生成和血管生成中起关键作用。它也是肿瘤生长、存活和癌细胞转移的重要蛋白质。在先前的一项研究中，我们已表明丙型肝炎病毒（HCV）感染可诱导人肝细胞发生上皮-间质转化（EMT）状态和癌症干细胞样（CSC）特性。我们的基因芯片数据表明，内皮糖蛋白（CD105）mRNA在HCV相关的CSC中显著上调。在本研究中，我们观察到在表达HCV核心蛋白的肝癌（HepG2）细胞系或永生化人肝细胞（IHH）的细胞表面，内皮糖蛋白表达增加，并且其下游信号分子被激活。在HCV感染的细胞或病毒核心基因转染的细胞中，磷酸化SMAD1/5的状态以及DNA结合蛋白1（ID1）的表达上调。此外，我们在慢性HCV患者肝活检样本中观察到内皮糖蛋白/ID1 mRNA表达上调。使用激活素受体样激酶1（ALK1）Fc阻断肽和内皮糖蛋白小干扰RNA（siRNA），由HCV核心蛋白产生CSC依赖于内皮糖蛋白信号通路。此外，后续分析表明，在HCV核心蛋白感染或异位表达期间，抗凋亡Bcl2蛋白、增殖相关的细胞周期蛋白D1蛋白以及CSC相关的Hes1、Notch1、Nanog和Sox2蛋白均增强。内皮糖蛋白在纤维生成和血管生成中起关键作用，是肿瘤生长、存活和癌细胞转移的重要蛋白质。内皮糖蛋白在不同细胞类型中增强ALK1-SMAD1/5信号传导，导致增殖和迁移反应增加。我们已观察到在源自人肝细胞的表达HCV核心蛋白的细胞表面有内皮糖蛋白表达，以及磷酸化SMAD1/5和ID1下游信号分子的激活。ID1蛋白在CSC特性中起作用，并且我们发现该途径对于抗凋亡和细胞增殖信号传导很重要。阻断内皮糖蛋白-ALK1-SMAD1/5可能是与肝硬化一起用于肝癌干细胞治疗的良好候选方案。
