Abstract
Human sulfatase-1 (hSulf-1) has been shown to desulfate cellular heparin sulfate proteoglycans and modulate several growth factors and cytokines. However, hSulf-1 has not been previously shown to mediate the signal transducer and activator of transcription 3 (stat3) signaling pathway, which is known to regulate cell proliferation, motility and apoptosis. The present study investigated the role of hSulf-1 in stat3 signaling in hepatocellular cancer. hSulf-1 expression vector and stat3 small interfering RNA (siRNA) were constructed to control the expression of hSulf-1 and stat3 in HepG2 cells. hSulf-1 was found to inhibit the phosphorylation of stat3 and downregulate its targeted protein. MTT and Transwell chamber assays, as well as Annexin V/propidium iodide double-staining methods, were used to examine the effects of hSulf-1 on stat3-mediated motility, proliferation and apoptosis in HepG2 cells. Transfection with hSulf-1 cDNA and/or stat3 siRNA inhibited cell proliferation and motility, concurrent with G0/G1 and G2/M phase cell cycle arrest and apoptosis. Overall, the results of the current study suggested that hSulf-1 functions as a negative regulator of proliferation and migration and as a positive regulator of apoptosis in hepatocellular carcinoma, at least partly via the downregulation of stat3 signaling.
Highlights
Hepatocellular carcinoma (HCC) is one of most common causes of cancer‐related mortality worldwide and the incidence of this cancer has been increasing in recent years (1,2)
While signal transducer and activator of transcription 3 signaling is known to be activated by several growth factor receptors, including epidermal growth factor receptor (EGFR) and platelet‐derived growth factor receptor (PDGFR), which are important in cell proliferation, migration, apoptosis and angiogenesis (19‐20), no previous studies have found a role for Human sulfatase 1 (hSulf‐1) in regulating the stat[3] signaling pathway
The stat[3] signaling pathway, which may be activated by several growth factor receptors, such as EGFR and PDGFR (19‐20), is known to be associated with the progression of HCC; the effects of hSulf‐1 on stat[3] signaling must be explored in HCC cells
Summary
Hepatocellular carcinoma (HCC) is one of most common causes of cancer‐related mortality worldwide and the incidence of this cancer has been increasing in recent years (1,2). Human sulfatase 1 (hSulf‐1), previously characterized as a heparin‐degrading endosulfatase, negatively regulates growth factor and cytokine signaling and proteolysis by desulfation of cell surface heparin sulfate proteoglycans (HSPGs), major constituents of the extracellular matrix (3‐6). This biological effect requires sulfation of defined sites on glycosaminoglycan chains. Previous studies have demonstrated that re‐expression of hSulf‐1 in ovarian cells suppresses fibroblast growth factor (FGF)‐2 and heparin‐binding epidermal growth factor (HB‐EGF) signaling and inhibits cell proliferation and invasion in vitro (11‐14). While signal transducer and activator of transcription 3 (stat3) signaling is known to be activated by several growth factor receptors, including epidermal growth factor receptor (EGFR) and platelet‐derived growth factor receptor (PDGFR), which are important in cell proliferation, migration, apoptosis and angiogenesis (19‐20), no previous studies have found a role for hSulf‐1 in regulating the stat[3] signaling pathway
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