Laboratory of Biology and Treatment of Metastases, Department of Oncology, Mario Negri Institute for Pharmacological Research, Milan, Italy.
Clin Exp Metastasis. 2010;27(1):43-53. doi: 10.1007/s10585-009-9301-8. Epub 2009 Dec 20.
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.
蛋白酶激活受体-1（PAR-1）是一种独特的 G 蛋白偶联受体，属于蛋白酶激活受体家族。其激活会引发下游信号事件，引发与肿瘤进展相关的各种细胞反应。PAR-1 的表达与多种人类癌症有关，我们之前的研究表明，与常见的痣相比，黑素瘤标本中 PAR-1 的表达更高。在本研究中，我们研究了 PAR-1 对源自皮肤原发性病变的人黑素瘤细胞系恶性表型的贡献，这些细胞系在源自其的患者中具有不同的转移行为。我们发现，源自患者转移性病变的黑素瘤细胞（WM115、WM278A、WM1361A、WM983A）的 PAR-1 mRNA 和蛋白表达水平高于源自无转移病变的细胞（WM793、WM35）。源自转移性原发性病变的细胞能够在免疫缺陷 SCID 小鼠的肺部定植，而源自非转移性病变的细胞则不能。此外，表达高 PAR-1 的细胞比表达最低 PAR-1 的细胞具有更高的迁移和侵袭能力。高表达 PAR-1 的黑素瘤细胞的迁移和侵袭能力受到基因和药理学干预的阻碍。用 siRNA 降低 PAR-1 表达和用特异性 PAR-1 拮抗剂 SCH79797 抑制 PAR-1 功能，显著降低了黑素瘤细胞的迁移和侵袭能力，降低程度与非转移性和低 PAR-1 表达细胞相似。我们的研究结果为 PAR-1 参与人类黑素瘤的恶性进展提供了有力证据。
