Dominant-negative CREB inhibits heparanase functionality and melanoma cell invasion

Rebecca Aucoin, Jane Reiland, Madhuchhanda Roy, Dario Marchetti

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

Heparanase (HPSE-1) is an endo-β-D-glucuronidase involved in the degradation of cell-surface/extracellular matrix heparan sulfate (HS) in normal and neoplastic tissues. HPSE-1 represents the first example of purification and cloning of a mammalian HS-degradative enzyme. Elevated HPSE-1 levels are known to be associated with metastatic cancers, directly implicating HPSE-1 in metastatic events. The purpose of this study was to determine the role of cAMP response element-binding protein (CREB) in modulating HPSE-1-mediated effects on human melanoma cell invasion. Highly invasive, brain-metastatic melanoma cells (70W) were transfected with the dominant-negative CREB (KCREB) and subsequently analyzed for changes in their HPSE-1 content, functionality, and cell invasive properties. KCREB-transfected cells showed a decrease in HPSE-1 mRNA expression and activity. This correlated with a significantly decreased invasion of these cells through Matrigel™-coated filters. Furthermore, adenoviral vectors containing the full-length human HPSE-1 cDNA in sense orientation (Ad-S/hep) were constructed to investigate CREB effects on HPSE-1. Restoration of HPSE-1 expression and functionality following Ad-S/hep infection of KCREB-transfected 70W cells recovered melanoma cell invasiveness. These results demonstrate that KCREB inhibits HPSE-1 and suggest that one of the roles CREB plays in the acquisition of melanoma cells metastatic phenotype is affecting HPSE-1 activity.

Original languageEnglish (US)
Pages (from-to)215-223
Number of pages9
JournalJournal of Cellular Biochemistry
Volume93
Issue number2
DOIs
StatePublished - 2004

Keywords

  • CREB
  • Dominant negative
  • Heparanase
  • Invasion
  • Malignant melanoma

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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