Abstract
BackgroundHuman 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.Principal FindingsTo 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.ConclusionsThe 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.
Highlights
Heparan sulfate proteoglycans (HSPGs) in extracellular matrix are important constituents for regulating the heparin-binding growth factor signaling, such as fibroblast growth factor (FGF), epidermal growth factor (EGF) and hepatocyte growth factor (HGF) [1,2]
The results demonstrated that Human sulfatase 1 (hSulf-1) re-expression both in ovarian and hepatocellular cancer cells induces antitumor efficacy by attenuating the phosphorylation of vascular endothelial growth factor receptor (VEGFR)-2 and suppressing angiogenesis
Human sulfatase 1 was characterized to be a heparin-degrading endosulfatase that functions to desulfate cell surface heparan sulfate proteoglycans (HSPGs) and negatively modulate growth factor and cytokine signaling [4]. hSulf-1 protein is widely expressed in normal tissue, but inactivated in majority of various human cancers, e.g., the ovarian, breast, pancreatic, renal, hepatic, head and neck squamous cell carcinomas [5,6,7]
Summary
Heparan sulfate proteoglycans (HSPGs) in extracellular matrix are important constituents for regulating the heparin-binding growth factor signaling, such as fibroblast growth factor (FGF), epidermal growth factor (EGF) and hepatocyte growth factor (HGF) [1,2]. Human sulfatase 1 (hSulf-1) was characterized to be a heparin-degrading endosulfatase that functions to desulfate cell surface HSPGs and negatively modulate growth factor and cytokine signaling [4]. The reported data suggested that hSulf-1 normally functions as a negative regulator in cell proliferation, it may play an important role in cancer therapy. 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. HSulf-1 function is more complicated, and its molecular mechanism has not been well known
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