Sulfatase 2 up-regulates glypican 3, promotes fibroblast growth factor signaling, and decreases survival in hepatocellular carcinoma

Authors

  • Jin-Ping Lai,

    Corresponding author
    1. Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    • Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905
    Search for more papers by this author
    • fax: 507-284-0762

  • Dalbir S. Sandhu,

    1. Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    Search for more papers by this author
  • Chunrong Yu,

    1. Department of Oncology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    Current affiliation:
    1. Roswell Park Cancer Institute, Buffalo, NY
    Search for more papers by this author
  • Tao Han,

    1. Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    Search for more papers by this author
  • Catherine D. Moser,

    1. Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    Search for more papers by this author
  • Kenard K. Jackson,

    1. Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    Search for more papers by this author
  • Ruben Bonilla Guerrero,

    1. Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    Search for more papers by this author
  • Ileana Aderca,

    1. Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    Search for more papers by this author
  • Hajime Isomoto,

    1. Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    Search for more papers by this author
  • Megan M. Garrity-Park,

    1. Department of Laboratory Medicine and Pathology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    Search for more papers by this author
  • Hongzhi Zou,

    1. Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    Search for more papers by this author
  • Abdirashid M. Shire,

    1. Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    Search for more papers by this author
  • David M. Nagorney,

    1. Division of Gastroenterologic and General Surgery, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    Search for more papers by this author
  • Schuyler O. Sanderson,

    1. Department of Laboratory Medicine and Pathology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    Search for more papers by this author
  • Alex A. Adjei,

    1. Department of Oncology, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    Current affiliation:
    1. Roswell Park Cancer Institute, Buffalo, NY
    Search for more papers by this author
  • Ju-Seog Lee,

    1. Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, MD
    Current affiliation:
    1. MD Anderson Cancer Center, Houston, TX
    Search for more papers by this author
  • Snorri S. Thorgeirsson,

    1. Laboratory of Experimental Carcinogenesis, National Cancer Institute, Bethesda, MD
    Search for more papers by this author
  • Lewis R. Roberts

    Corresponding author
    1. Miles and Shirley Fiterman Center for Digestive Diseases, College of Medicine, Mayo Clinic and Mayo Clinic Cancer Center, Rochester, MN
    • Miles and Shirley Fiterman Center for Digestive Diseases, Mayo Clinic, 200 First Street SW, Rochester, MN 55905
    Search for more papers by this author
    • fax: 507-284-0762.


  • Potential conflict of interest: Nothing to report.

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. Conclusion: 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. (HEPATOLOGY 2008.)

Ancillary