Protease-activated receptor-1 (PAR-1) promotes the motility of human melanomas and is associated to their metastatic phenotype.
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.
Silini
Antonietta
A
Laboratory of Biology and Treatment of Metastases, Department of Oncology, Mario Negri Institute for Pharmacological Research, Milan, Italy.
Ghilardi
Carmen
C
Ardinghi
Camilla
C
Bernasconi
Sergio
S
Oliva
Paolo
P
Carraro
Fabio
F
Naldini
Antonella
A
Bani
Maria Rosa
MR
Giavazzi
Raffaella
R
D000818:Animals; D045744:Cell Line, Tumor; D002465:Cell Movement; D018450:Disease Progression; D006801:Humans; D008545:Melanoma / Q000378:metabolism / Q000473:pathology; D051379:Mice; D016513:Mice, SCID; D009362:Neoplasm Metastasis; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D044463:Receptor, PAR-1 / Q000378:metabolism / Q000502:physiology*; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology
C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D011758:Pyrroles; D011799:Quinazolines; D044463:Receptor, PAR-1