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 Rowland Roberts, Vijayalakshmi Shridhar

Research output: Contribution to journalArticle

103 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

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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
  • Cancer Research
  • Genetics

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