title: hSulf-1 gene exhibits anticancer efficacy through negatively regulating VEGFR-2 signaling in human cancers.
abstract: BACKGROUND
  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. But hSulf-1 function is more complicated, and its molecular mechanism has not been well known.
  
  
  RESULTS
  To 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.
  
  
  CONCLUSIONS
  The 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.
authors.affiliation: Department of Molecular Oncology, Eastern Hepatobiliary Surgical Hospital & Institute, The Second Military Medical University, Shanghai, China.
authors.forename: Weidan
authors.initials: W
authors.lastname: Ji
authors.forename: Jiahe
authors.initials: J
authors.lastname: Yang
authors.forename: Duanming
authors.initials: D
authors.lastname: Wang
authors.forename: Lu
authors.initials: L
authors.lastname: Cao
authors.forename: Weifeng
authors.initials: W
authors.lastname: Tan
authors.forename: Haihua
authors.initials: H
authors.lastname: Qian
authors.forename: Bin
authors.initials: B
authors.lastname: Sun
authors.forename: Qijun
authors.initials: Q
authors.lastname: Qian
authors.forename: Zhengfeng
authors.initials: Z
authors.lastname: Yin
authors.forename: Mengchao
authors.initials: M
authors.lastname: Wu
authors.forename: Changqing
authors.initials: C
authors.lastname: Su
mesh_terms: D000256:Adenoviridae; D020533:Angiogenesis Inhibitors / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015536:Down-Regulation; D004789:Enzyme Activation; D015316:Genetic Therapy; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009369:Neoplasms / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D010766:Phosphorylation; D015398:Signal Transduction; D015238:Sulfotransferases / Q000235:genetics* / Q000627:therapeutic use*; D016896:Treatment Outcome; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays
chemical_list: D020533:Angiogenesis Inhibitors; D000970:Antineoplastic Agents; D040301:Vascular Endothelial Growth Factor Receptor-2; C470791:SULF1 protein, human; D015238:Sulfotransferases