HSulf-1 modulates HGF-mediated tumor cell invasion and signaling in head and neck squamous carcinoma

Jin Ping Lai, Jeremy Chien, Scott E. Strome, Julie Staub, Damian P. Montoya, Eddie L. Greene, David I. Smith, Lewis R. Roberts, Viji Shridhar

Research output: Contribution to journalArticlepeer-review

112 Scopus citations

Abstract

Recently, we cloned a novel sulfatase domain-containing downregulated gene, HSulf-1, which modulates heparin-binding growth factor signaling in ovarian cancer. Based on the pilot data showing the loss of HSulf-1 in head and neck squamous cell carcinoma cell lines (SCCHN), we sought to employ SCCHN as a model to define the role of HSulf-1 in the molecular regulation of tumorigenecity. Three SCCHN lines (012SCC, WMMSCC, and 015SCC) had no detectable HSulf-1 mRNA. Clonal lines of HSulf-1-expressing 012SCC attenuated the activation of ERK/mitogen-activated protein kinase (MAPK) signaling mediated by fibroblast growth factor (FGF-2) and both ERK/MAPK and Akt signaling mediated by hepatocyte growth factor (HGF). Consistent with this downregulation, phosphorylation of HGF receptor, c-Met, which is frequently overexpressed in SCCHN, was also attenuated in HSulf-1 clonal 012SCC cell lines. HGF markedly enhanced the motility and migration of vector-transfected cells in a transwell invasion chamber. However, HGF-mediated motility and invasion was attenuated in HSulf-1 clonal 012SCC cell lines. In addition, transfected cells displayed significant growth inhibition concomitant with a decrease in mitogenecity, as measured by thymidine incorporation and increased sensitivity to staurosporine- and cisplatin-induced apoptosis. These data suggest that HSulf-1 normally functions as a negative regulator in cell growth and loss of HSulf-1 in SCCHN potentiates growth factor signaling, enhances motility, invasiveness and inhibits stress-induced apoptosis, with a resulting increase in tumorigenecity.

Original languageEnglish (US)
Pages (from-to)1439-1447
Number of pages9
JournalOncogene
Volume23
Issue number7
DOIs
StatePublished - Feb 19 2004
Externally publishedYes

Keywords

  • Apoptosis
  • Head and neck squamous carcinoma
  • Heparan sulfate glycosaminoglycans
  • Heparin-binding growth factors
  • Hepatocyte growth factor
  • Tumor cell invasion

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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