Antisense-mediated suppression of heparanase gene inhibits melanoma cell invasion

Madhuchhanda Roy, Jane Reiland, Brian P. Murry, Vladimir Chouljenko, Konstantin G. Kousoulas, Dario Marchetti

Research output: Contribution to journalArticlepeer-review

53 Scopus citations

Abstract

Cancer metastasis is a frequent manifestation of malignant melanoma progression. Successful invasion into distant organs by tumor cells must include attachment to microvessel endothelial cells, and degradation of basement membranes and extracellular matrix (ECM). Heparan sulfate proteoglycans (HSPG) are essential and ubiquitous macromolecules associated with the cell surface and ECM of a wide range of cells and tissues. Heparanase (HPSE-1) is an ECM degradative enzyme, which degrades the heparan sulfate (HS) chains of HSPG at specific intrachain sites. To investigate effects of changes in heparanase gene expression in metastatic melanoma cells, we constructed adenoviral vectors containing the full-length human HPSE-1 cDNA in both sense (Ad-S/hep) and antisense orientations (Ad-AS/hep). We found increased HPSE-1 expression and activity in melanoma cell lines following Ad-S/hep infection by Western blot analyses and specific HPSE-1 activity assay. Conversely, HPSE-1 content was significantly inhibited following infection with Ad-AS/Hep. Importantly, HPSE-1 modulation by these adenoviral constructs correlated with invasive cellular properties in vitro and in vivo. Our results suggest that HPSE-1 not only contributes to the invasive phenotype of melanoma cells, but also that the Ad-AS/hep-mediated inhibition of its enzymatic activity can be efficacious in the prevention and treatment of melanoma metastasis.

Original languageEnglish (US)
Pages (from-to)253-262
Number of pages10
JournalNeoplasia
Volume7
Issue number3
DOIs
StatePublished - Mar 2005

Keywords

  • Anti-sense gene delivery
  • Heparan sulfate
  • Heparanase
  • Invasion and metastasis
  • Malignant melanoma

ASJC Scopus subject areas

  • Cancer Research

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