title: HSulf-1 inhibits cell proliferation and invasion in  human gastric cancer.
abstract: 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.
authors: School of Life Sciences, Tsinghua University, Beijing, China.
authors: Jie
authors: J
authors: Li
authors: Min-Li
authors: ML
authors: Mo
authors: Zhao
authors: Z
authors: Chen
authors: Jie
authors: J
authors: Yang
authors: Qiu-Shi
authors: QS
authors: Li
authors: Dian-Jun
authors: DJ
authors: Wang
authors: Hui
authors: H
authors: Zhang
authors: Ying-Jiang
authors: YJ
authors: Ye
authors: Hai-Long
authors: HL
authors: Li
authors: Fang
authors: F
authors: Zhang
authors: Hai-Meng
authors: HM
authors: Zhou
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D019812:Heparan Sulfate Proteoglycans / Q000378:metabolism; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009361:Neoplasm Invasiveness; D009368:Neoplasm Transplantation; D013274:Stomach Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D015238:Sulfotransferases / Q000235:genetics* / Q000378:metabolism*; D014158:Transcription, Genetic; D015533:Transcriptional Activation; D014183:Transplantation, Heterologous; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D019812:Heparan Sulfate Proteoglycans; D008565:Membrane Proteins; D051153:Wnt Proteins; D051176:beta Catenin; C470791:SULF1 protein, human; D015238:Sulfotransferases