Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & Institute, The Second Military Medical University, Shanghai, China.
PLoS One. 2011;6(8):e23274. doi: 10.1371/journal.pone.0023274. Epub 2011 Aug 10.
Human sulfatase 1 (hSulf-1) is a heparin-degrading endosulfatase that desulfates cell surface heparan sulfate proteoglycans (HSPGs) in extracellular matrix and negatively modulates heparin-binding growth factor and cytokine signaling in cell proliferation. But hSulf-1 function is more complicated, and its molecular mechanism has not been well known.
To further investigate the functions of hSulf-1 gene in regulating the vascular endothelial growth factor receptor (VEGFR) signaling, a series of vectors expressing hSulf-1, hSulf-1 small hairpin RNA (shRNA) and VEGFR-2 shRNA were generated. hSulf-1 re-expression could downregualte the VEGFR-2 phosphorylation and inhibit cancer cell proliferation both in ovarian and hepatocellular cancer cell lines. Knockdown of hSulf-1 expression by hSulf-1 shRNA enhanced the recovery of high levels of phosphorylated VEGFR-2, and knockdown of VEGFR-2 expression by VEGFR-2 shRNA inhibited the proliferation activity of cancer cells in vitro to some extent. In human cancer xenografts in nude mice, tumor growth was inhibited markedly after injections of adenovirus expressing hSulf-1, with the tumor inhibition rates of 46.19% and 49.56% in ovarian and hepatocellular tumor models, respectively. hSulf-1 expression significantly reduced tumor microvessel density.
The results demonstrated that hSulf-1 re-expression both in ovarian and hepatocellular cancer cells induces antitumor efficacy by attenuating the phosphorylation of VEGFR-2 and suppressing angiogenesis. Therefore, hSulf-1-mediated antiproliferation and antiangiogenesis could be a reasonable approach for cancer therapy.
人源硫酸酯酶 1（hSulf-1）是一种肝素降解内切硫酸酯酶，可使细胞表面硫酸乙酰肝素蛋白聚糖（HSPGs）去硫酸化，负调控细胞增殖过程中肝素结合生长因子和细胞因子信号。但 hSulf-1 的功能更为复杂，其分子机制尚未完全明确。
为进一步研究 hSulf-1 基因在调节血管内皮生长因子受体（VEGFR）信号中的作用，构建了一系列表达 hSulf-1、hSulf-1 短发夹 RNA（shRNA）和 VEGFR-2 shRNA 的载体。hSulf-1 的重新表达可下调 VEGFR-2 的磷酸化，并抑制卵巢癌细胞系和肝癌细胞系的癌细胞增殖。hSulf-1 shRNA 下调 hSulf-1 表达可增强高磷酸化 VEGFR-2 的恢复，而 VEGFR-2 shRNA 下调 VEGFR-2 表达可在一定程度上抑制癌细胞的体外增殖活性。在裸鼠人源肿瘤异种移植模型中，表达 hSulf-1 的腺病毒注射后，肿瘤生长明显受到抑制，卵巢癌和肝癌模型的肿瘤抑制率分别为 46.19%和 49.56%。hSulf-1 的表达显著降低了肿瘤微血管密度。
这些结果表明，hSulf-1 在卵巢癌和肝癌细胞中的重新表达通过减弱 VEGFR-2 的磷酸化和抑制血管生成来诱导抗肿瘤疗效。因此，hSulf-1 介导的增殖抑制和血管生成抑制可能是癌症治疗的一种合理方法。
