Clinical & Experimental Metastasis

, Volume 27, Issue 1, pp 43–53

Protease-activated receptor-1 (PAR-1) promotes the motility of human melanomas and is associated to their metastatic phenotype

  • Antonietta Silini
  • Carmen Ghilardi
  • Camilla Ardinghi
  • Sergio Bernasconi
  • Paolo Oliva
  • Fabio Carraro
  • Antonella Naldini
  • Maria Rosa Bani
  • Raffaella Giavazzi
Research Paper

DOI: 10.1007/s10585-009-9301-8

Cite this article as:
Silini, A., Ghilardi, C., Ardinghi, C. et al. Clin Exp Metastasis (2010) 27: 43. doi:10.1007/s10585-009-9301-8

Abstract

Protease-activated receptor-1 (PAR-1) is a unique G-protein-coupled receptor belonging to the protease-activated receptor family. Its activation leads to downstream signaling events that launch a variety of cellular responses related to tumor progression. PAR-1 expression has been associated to a variety of human cancers, and our previous studies reveal a high PAR-1 expression in melanoma specimens as compared to common nevi. In the present study, we investigated the contribution of PAR-1 to the malignant phenotype of human melanoma cell lines obtained from cutaneous primary lesions, capable of different metastatic behaviors in the patients from which they have been derived. We found that melanoma cells isolated from lesions giving rise to metastases in patients (WM115, WM278A, WM1361A, WM983A), had higher PAR-1 mRNA and protein expression, as compared to those obtained from lesions that did not develop metastatic disease (WM793, WM35). The cells isolated from metastatic primary lesions were able to colonize the lungs of immunodeficient SCID mice while those isolated from non-metastatic lesions were not. Additionally, cells expressing elevated PAR-1 had higher migratory and invasive abilities than those holding minimal PAR-1 expression. The migration and invasion capabilities of the melanoma cells expressing high PAR-1 were hampered by genetic and pharmacological interventions. The reduction of PAR-1 expression by siRNA and the inhibition of PAR-1 function by the SCH79797 specific antagonist significantly decreased the melanoma cell motility and invasiveness, down to an extent similar to that of the non-metastatic and low PAR-1 expressing cells. Our results provide strong evidence supporting the implication of PAR-1 in the malignant progression of human melanoma.

Keywords

Invasion Malignant melanoma Metastasis Migration Protease-activated receptor-1 (PAR-1) 

Supplementary material

10585_2009_9301_MOESM1_ESM.doc (64 kb)
Supplementary material 1 (DOC 64 kb)

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  • Antonietta Silini
    • 1
  • Carmen Ghilardi
    • 1
  • Camilla Ardinghi
    • 2
  • Sergio Bernasconi
    • 3
  • Paolo Oliva
    • 1
  • Fabio Carraro
    • 2
  • Antonella Naldini
    • 2
  • Maria Rosa Bani
    • 1
  • Raffaella Giavazzi
    • 1
  1. 1.Laboratory of Biology and Treatment of Metastases, Department of OncologyMario Negri Institute for Pharmacological ResearchMilanItaly
  2. 2.Department of PhysiologyUniversity of SienaSienaItaly
  3. 3.Flow Cytometry Unit, Department of OncologyMario Negri Institute for Pharmacological ResearchMilanItaly