Xu Gaoya, Ji Weidan, Su Yinghan, Xu Yang, Yan Yan, Shen Shuwen, Li Xiaoya, Sun Bin, Qian Haihua, Chen Lei, Fu Xiaohui, Wu Mengchao, Su Changqing
Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, The Second Military Medical University, Shanghai, China. Department of Pathogen Biology, School of Biology & Basic Medical Sciences, Soochow University, Suzhou, China.
Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & National Center of Liver Cancer, The Second Military Medical University, Shanghai, China.
Oncotarget. 2014 Jul 15;5(13):5029-39. doi: 10.18632/oncotarget.2078.
The human sulfatase 1 (hSulf-1) gene encodes an endosulfatase that functions to inhibit the heparin-binding growth factor signaling, including the basic fibroblast growth factor (bFGF)-mediated pathway, by desulfating the cell surface heparan sulfate proteoglycans (HSPGs). bFGF could stimulate cell cycle progression and inhibit cell apoptosis, this biological effect can be reversed by hSulf-1. However, molecular mechanisms have not been fully reported. In the current study, by reactivation of hSulf-1 expression and function in the hSulf-1-negative hepatocellular carcinoma (HCC) cell lines and HCC xenograft tumors, we found that hSulf-1 blocked the bFGF effect on the promotion of cell cycle and inhibition of apoptosis. The bFGF-stimulated activation of protein kinase B (AKT) and extracellular signal-regulated kinase (ERK) pathways was suppressed by hSulf-1, which led to a decreased expression of the target genes Cyclin D1 and Survivin, then finally induced cell cycle arrest and apoptosis in HCC cells. Our data suggested that hSulf-1 may be a suitable target for cancer therapy.
人类硫酸酯酶1（hSulf-1）基因编码一种内硫酸酯酶，该酶通过使细胞表面硫酸乙酰肝素蛋白聚糖（HSPG）去硫酸化，发挥抑制肝素结合生长因子信号传导的作用，包括抑制碱性成纤维细胞生长因子（bFGF）介导的信号通路。bFGF可刺激细胞周期进程并抑制细胞凋亡，而hSulf-1可逆转这种生物学效应。然而，其分子机制尚未完全报道。在本研究中，通过在hSulf-1阴性的肝癌（HCC）细胞系和HCC异种移植瘤中重新激活hSulf-1的表达和功能，我们发现hSulf-1可阻断bFGF对细胞周期的促进作用和对细胞凋亡的抑制作用。hSulf-1抑制了bFGF刺激的蛋白激酶B（AKT）和细胞外信号调节激酶（ERK）信号通路的激活，这导致靶基因细胞周期蛋白D1（Cyclin D1）和生存素（Survivin）的表达降低，最终诱导HCC细胞的细胞周期停滞和凋亡。我们的数据表明，hSulf-1可能是癌症治疗的一个合适靶点。
