Expression of protease-activated receptors 1 and 2 in melanocytic nevi and malignant melanoma

Massi, Daniela; Naldini, Antonella; Ardinghi, C; Carraro, Fabio; Franchi, Alessandro; Paglierani, Milena; Tarantini, Francesca; Ketabchi, Sheyda; Cirino, Giuseppe; Hollenberg, Morley D.; Geppetti, Pierangelo; Santucci, Marco

doi:10.1016/j.humpath.2005.04.008

Cited by 65 publications

(75 citation statements)

References 37 publications

(41 reference statements)

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“…Several reports indicate that thrombin participates in melanoma growth and metastasis. 38 We have recently reported that thrombin receptor PAR-1 is unregulated in the initial phases of melanocytic tumor transformation and progression 39 and it has been shown that in cutaneous melanoma, loss of expression of the transcription factor activator protein-2a (AP-2), correlates with overexpression of PAR-1 and the acquisition of a malignant phenotype. 40 Thus, it may be proposed that thrombin participates in melanoma progression by different signaling pathways, including PAR-1 and Jagged-1 cleavage.…”

Section: Expression Of Notch Receptors and Their Ligands In Cutaneousmentioning

confidence: 99%

Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma

et al. 2006

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Section: Expression Of Notch Receptors and Their Ligands In Cutaneousmentioning

confidence: 99%

Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma

et al. 2006

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“…Thrombin binds PAR-1 and mediates increased invasiveness and metastatic potential of cancer cells [33][34][35] and enhanced cancer cell adhesion to platelets [36][37][38], endothelial cells [39], fibronectin and Von Willebrand factor [12,37]. Inhibition of thrombin by Hirudin may switch off PAR-1 signalling resulting in decreased tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung

Niers

Brüggemann

Klerk

et al. 2008

Clin Exp Metastasis

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Cancer progression is facilitated by blood coagulation. Anticoagulants, such as Hirudin and low molecular weight heparins (LMWHs), reduce metastasis mainly by inhibition of thrombin formation and L-and Pselectin-mediated cell-cell adhesion. It is unknown whether the effects are dependent on cancer cell type. The effects of anticoagulants on tumor development of K1735 and B16 melanoma cells and CT26 colon cancer cells were investigated in mouse lung. Tumor load was determined noninvasively each week up to day 21 in all experiments using bioluminescence imaging. Effects of anticoagulants on tumor development of the three cell lines were correlated with the fibrin/fibrinogen content in the tumors, expression of tissue factor (TF), protease activated receptor (PAR)-1 and -4 and CD24, a ligand of L-and P-selectins. Hirudin inhibited tumor development of B16 cells in lungs completely but did not affect tumor growth of K1735 and CT26 cells. Low molecular weight heparin did not have an effect on K1735 melanoma tumor growth either. TF and PAR-4 expression was similar in the three cell lines. PAR-1 and CD24 were hardly expressed by K1735, whereas CT26 cells expressed low levels and B16 high levels of PAR-1 and CD24. Fibrin content of the tumors was not affected by LMWH. It is concluded that effects of anticoagulants are dependent on cancer cell type and are correlated with their CD24 and PAR-1 expression.Keywords B16 melanoma Á CT26 colon carcinoma Á K1735 melanoma Á Hirudin Á Low molecular weight heparin Á Selectin Á PAR

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“…Furthermore, we and others have shown that melanoma tumors have increased PAR-1 expression compared with nevi (5,6). Recently, we demonstrated that systemic delivery of PAR-1 siRNA encapsulated into neutral nanoliposomes inhibited tumor growth and experimental lung metastasis of melanoma cells in vivo (7).…”

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confidence: 83%

Protease activated receptor-1 inhibits the Maspin tumor-suppressor gene to determine the melanoma metastatic phenotype

Villares

Zigler

Dobroff

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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The thrombin receptor protease activated receptor-1 (PAR-1) is overexpressed in metastatic melanoma cell lines and tumor specimens. Previously, we demonstrated a significant reduction in tumor growth and experimental lung metastasis after PAR-1 silencing via systemic delivery of siRNA encapsulated into nanoliposomes. Gene expression profiling identified a 40-fold increase in expression of Maspin in PAR-1-silenced metastatic melanoma cell lines. Maspin promoter activity was significantly increased after PAR-1 silencing, suggesting that PAR1 negatively regulates Maspin at the transcriptional level. ChIP analyses revealed that PAR-1 decreases binding of Ets-1 and c-Jun transcription factors to the Maspin promoter, both known to activate Maspin transcription. PAR-1 silencing did not affect Ets-1 or c-Jun expression; rather it resulted in increased expression of the chromatin remodeling complex CBP/p300, as well as decreased activity of the CBP/p300 inhibitor p38, resulting in increased binding of Ets-1 and c-Jun to the Maspin promoter and higher Maspin expression. Functionally, Maspin expression reduced the invasive capability of melanoma cells after PAR-1 silencing, which was abrogated after rescuing with PAR-1. Furthermore, tumor growth and experimental lung metastasis was significantly decreased after expressing Maspin in a metastatic melanoma cell line. Moreover, silencing Maspin in PAR-1-silenced cells reverted the inhibition of tumor growth and experimental lung metastasis. Herein, we demonstrate a mechanism by which PAR-1 negatively regulates the expression of the Maspin tumor-suppressor gene in the acquisition of the metastatic melanoma phenotype, thus attributing an alternative function to PAR-1 other than coagulation. melanoma progression | transcriptional regulation | G protein-coupled receptor signaling | Serpin B5

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Expression of protease-activated receptors 1 and 2 in melanocytic nevi and malignant melanoma

Cited by 65 publications

References 37 publications

Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma

Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma

Differential effects of anticoagulants on tumor development of mouse cancer cell lines B16, K1735 and CT26 in lung

Protease activated receptor-1 inhibits the Maspin tumor-suppressor gene to determine the melanoma metastatic phenotype

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