Human Monoclonal Antibody Targeting the Heparan Sulfate Chains of Glypican-3 Inhibits HGF-Mediated Migration and Motility of Hepatocellular Carcinoma Cells.
Human Monoclonal Antibody Targeting the Heparan Sulfate Chains of Glypican-3 Inhibits HGF-Mediated Migration and Motility of Hepatocellular Carcinoma Cells.
复制标题
DOI：
10.1371/journal.pone.0137664
复制
发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Ho M
中科院分区：
文献类型：
--
作者：
Gao W;Kim H;Ho M
硫酸乙酰肝素蛋白聚糖（HSPG）参与了许多与肿瘤发生、转移有关的过程。HSPG含有一个或多个与核心蛋白共价连接的硫酸乙酰肝素（HS）链。磷脂酰肌醇蛋白聚糖3（Glypican-3，GPC 3）是一种在肝细胞癌（Hepatocellular carcinoma，HCC）中高表达的细胞表面相关的热休克蛋白G。GPC 3参与Wnt 3a依赖性HCC细胞增殖。我们先前的研究报道了靶向GPC 3上HS链的人单克隆抗体HS 20抑制Wnt 3a/β-catenin活化。在本研究中，我们发现GPC 3的HS链可以介导HCC细胞的迁移和运动。通过HS 20敲除GPC 3或靶向HS链抑制HCC细胞的迁移和运动。然而，HS 20对GPC 3敲低细胞或GPC 3阴性细胞没有影响。此外，识别GPC 3核心蛋白的抗体不改变细胞运动速率。HCC细胞迁移和运动性对经典或非经典Wnt诱导均无反应，但在肝细胞生长因子（HGF）处理下确实增加。HS 20处理的HCC细胞表现出较低的HGF介导的迁移和运动能力。此外，HS 20抑制体外HCC球体形成和小鼠肝肿瘤生长。GPC 3与HGF相互作用;然而，缺乏HS链的突变GPC 3与HGF的相互作用较少。用HS 20阻断GPC 3上的HS链减少了HGF处理的HCC细胞和3D培养的球状体中的c-Met活化。总之，我们的研究表明，GPC 3通过HS链介导的与HGF/Met通路的合作参与HCC细胞的迁移和运动，显示了HS靶向如何对肝癌具有潜在的治疗意义。
Heparan sulfate proteoglycans (HSPGs) participate in many processes related to tumor development, including tumorigenesis and metastasis. HSPGs contain one or more heparan sulfate (HS) chains that are covalently linked to a core protein. Glypican-3 (GPC3) is a cell surface-associated HSPG that is highly expressed in hepatocellular carcinoma (HCC). GPC3 is involved in Wnt3a-dependent HCC cell proliferation. Our previous study reported that HS20, a human monoclonal antibody targeting the HS chains on GPC3, inhibited Wnt3a/β-catenin activation. In the current study, we showed that the HS chains of GPC3 could mediate HCC cells’ migration and motility. Knocking down GPC3 or targeting the HS chains by HS20 inhibited HCC cell migration and motility. However, HS20 had no effect on GPC3 knockdown cells or GPC3 negative cells. In addition, an antibody that recognizes the core protein of GPC3 did not change the rate of cell motility. HCC cell migration and motility did not respond to either canonical or non-canonical Wnt induction, but did increase under hepatocyte growth factor (HGF) treatment. HS20-treated HCC cells exhibited less ability for HGF-mediated migration and motility. Furthermore, HS20 inhibited in vitro HCC spheroid formation and liver tumor growth in mice. GPC3 interacted with HGF; however, a mutant GPC3 lacking the HS chain showed less interaction with HGF. Blocking the HS chains on GPC3 with HS20 reduced c-Met activation in HGF-treated HCC cells and 3D-cultured spheroids. Taken together, our study suggests that GPC3 is involved in HCC cell migration and motility through HS chain-mediated cooperation with the HGF/Met pathway, showing how HS targeting has potential therapeutic implications for liver cancer.