title: Sulfatase 2 up-regulates glypican 3, promotes fibroblast growth factor signaling, and decreases survival in hepatocellular carcinoma.
abstract: It has been shown that the heparin-degrading endosulfatase, sulfatase 1 (SULF1), functions as a liver tumor suppressor, but the role of the related sulfatase, sulfatase 2 (SULF2), in liver carcinogenesis remains to be elucidated. We investigated the effect of SULF2 on liver tumorigenesis. Expression of SULF2 was increased in 79 (57%) of 139 hepatocellular carcinomas (HCCs) and 8 (73%) of 11 HCC cell lines. Forced expression of SULF2 increased HCC cell growth and migration, whereas knockdown of SULF2 using short hairpin RNA targeting SULF2 abrogated HCC cell proliferation and migration in vitro. Because SULF1 and SULF2 desulfate heparan sulfate proteoglycans (HSPGs) and the HSPG glypican 3 (GPC3) is up-regulated in HCC, we investigated the effects of SULF2 on GPC3 expression and the association of SULF2 with GPC3. SULF2-mediated cell growth was associated with increased binding of fibroblast growth factor 2 (FGF2), phosphorylation of extracellular signal-regulated kinase and AKT, and expression of GPC3. Knockdown of GPC3 attenuated FGF2 binding in SULF2-expressing HCC cells. The effects of SULF2 on up-regulation of GPC3 and tumor growth were confirmed in nude mouse xenografts. Moreover, HCC patients with increased SULF2 expression in resected HCC tissues had a worse prognosis and a higher rate of recurrence after surgery.
  
  
  CONCLUSIONS
  In contrast to the tumor suppressor effect of SULF1, SULF2 has an oncogenic effect in HCC mediated in part through up-regulation of FGF signaling and GPC3 expression.
authors.affiliation: Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN 55905, USA. lai.jinping@mayo.edu
authors.forename: Jin-Ping
authors.initials: JP
authors.lastname: Lai
authors.forename: Dalbir S
authors.initials: DS
authors.lastname: Sandhu
authors.forename: Chunrong
authors.initials: C
authors.lastname: Yu
authors.forename: Tao
authors.initials: T
authors.lastname: Han
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Moser
authors.forename: Kenard K
authors.initials: KK
authors.lastname: Jackson
authors.forename: Ruben Bonilla
authors.initials: RB
authors.lastname: Guerrero
authors.forename: Ileana
authors.initials: I
authors.lastname: Aderca
authors.forename: Hajime
authors.initials: H
authors.lastname: Isomoto
authors.forename: Megan M
authors.initials: MM
authors.lastname: Garrity-Park
authors.forename: Hongzhi
authors.initials: H
authors.lastname: Zou
authors.forename: Abdirashid M
authors.initials: AM
authors.lastname: Shire
authors.forename: David M
authors.initials: DM
authors.lastname: Nagorney
authors.forename: Schuyler O
authors.initials: SO
authors.lastname: Sanderson
authors.forename: Alex A
authors.initials: AA
authors.lastname: Adjei
authors.forename: Ju-Seog
authors.initials: JS
authors.lastname: Lee
authors.forename: Snorri S
authors.initials: SS
authors.lastname: Thorgeirsson
authors.forename: Lewis R
authors.initials: LR
authors.lastname: Roberts
mesh_terms: D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000201:enzymology*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D049109:Cell Proliferation; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism*; D053673:Glypicans / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis / Q000201:enzymology*; D051379:Mice; D008819:Mice, Nude; D011379:Prognosis; D015398:Signal Transduction / Q000502:physiology; D013429:Sulfatases; D015238:Sulfotransferases / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D053673:Glypicans; D016222:Fibroblast Growth Factor 2; D015238:Sulfotransferases; C470792:SULF2 protein, human; D013429:Sulfatases