Abstract
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.
Highlights
Survival of cancer cells depends on the activation of a series of signaling pathways
Our previous study showed that human sulfatase 1 (hSulf-1) is inactivated in majority of human cancers including hepatocellular, breast, gastric, renal and colon cancers, compared with their adjacent normal tissues, and reactivation of hSulf-1 can suppress cancer cell proliferation and xenograft tumor growth by inhibiting the activity of extracellular signal-regulated kinase (ERK) and AKT signaling pathways [11,12]
The basic fibroblast growth factor (bFGF) expression can promote cancer cell proliferation by activating the PI3K/AKT and MAPK/ ERK pathways in cancer [14,15]. bFGF binds its receptor on cell surface and activates the downstream signaling pathways, functions the mitogenic activity and promotes cancer cell cycle progression [16,17,18,19]
Summary
Survival of cancer cells depends on the activation of a series of signaling pathways. BFGF is considered to play an important role in stimulating the proliferation of various cancer cells It can induce cancer cell proliferation by activating or expressing G1-S phase proteins, including E2F-1, cdks and cyclins, through the reactive oxygen species/phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway in colon cancer [14,15]. Since hSulf-1 plays a negative regulatory role in bFGF signaling pathways, and bFGF functions to promote cell cycle progression in human cancers as aforementioned, it is supposed that hSulf-1 can regulate cancer cell cycle and control cancer programmed cell death, such as apoptosis. BFGF was used to stimulate the cell cycle progression in HCC cell lines, hSulf-1 was re-expressed by adenoviral vector to block the bFGF-mediated signaling pathways, and the regulatory effects and mechanisms of hSulf-1 on HCC cell cycle control were investigated in the in vitro experiments. This study gave a new insight into the function of hSulf-1 as a negative regulator of cell cycle, which will help to design a novel strategy of hSulf-1 gene therapy in HCC target treatment
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