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HSulf‐1 inhibits cell proliferation and invasion in human gastric cancer

The HSulf‐1 gene encodes an extracellular 6‐O‐endosulfatase and regulates the sulfation status of heparan sulfate proteoglycans (HSPG). We have demonstrated that promoter hypermethylation is correlated with the HSulf‐1 silencing in gastric cancer. To investigate the functional importance of HSulf‐1 silencing in gastric cancer, we restored HSulf‐1 expression in the gastric cancer cell line MKN28, which lacks endogenous HSulf‐1. Following restoration of expression, HSulf‐1 inhibited cell proliferation, motility, and invasion in vitro, as well as significantly suppressing the MKN28 xenograft model (P < 0.05). No noticeable changes in proliferation and motility were observed following restoration of HSulf‐1 in another gastric cancer cell line, namely AGS cells. Interestingly, in MKN28 cells, which have been reported to be dependent on extracellular Wnt signaling, we found that HSulf‐1 inhibited the transcriptional activity of the Wnt/β‐catenin pathway and downregulated its targeted genes. Conversely, in AGS cells, in the constitutive Wnt/β‐catenin pathway is active, HSulf‐1 had no effect on the activity of the Wnt/β‐catenin pathway. Furthermore, transfection of Wnt3a cDNA or β‐catenin shRNA resulted in rescue or enhancement, respectively, of the effects of HSulf‐1 in MKN28 cells. Furthermore, HSPG epitope analysis confirmed that HSulf‐1 affected the structure of heparan sulfate on the cell surface. Together, the results of the present study suggest that extracellular HSulf‐1 may function as a negative regulator of proliferation and invasion in gastric cancer by suppressing Wnt/β‐catenin signaling at the cell surface. (Cancer Sci 2011; 102: 1815–1821)