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

Villares, Gabriel J.; Zigler, Maya; Dobroff, Andrey S.; Wang, Hua; Song, Renduo; Melnikova, Vladislava O.; Huang, Li; Braeuer, Russell R.; Bar‐Eli, Menashe

doi:10.1073/pnas.1006886108

Cited by 45 publications

(40 citation statements)

References 39 publications

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“…The thrombin receptor, protease-activated receptor-1, which is overexpressed in metastatic melanoma cell lines and tumor specimens, plays a key role in serving this function during melanoma progression. Recently, pro- tease-activated receptor-1 has been reported to regulate the gap junction protein connexin 43 and the tumor suppressor gene maspin to promote the metastatic melanoma phenotype [26][27][28].…”

Section: Discussionmentioning

confidence: 99%

Clinical and prognostic significance of coagulation assays in melanoma

et al. 2012

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The activation of coagulation and fibrinolysis is frequently found among cancer patients. Such tumors are considered to be associated with a higher risk of invasion, metastases, and eventually worse outcome. The aim of this study is to explore the clinical and prognostic value of blood coagulation tests for melanoma patients. Pretreatment blood coagulation tests including prothrombin time (PT), activated partial thromboplastin time (APTT), prothrombin activity (PTA), international normalized ratio (INR), D-dimer (DD), fibrinogen (F) levels, and platelet (PLT) counts were carried out. This prospective study included 61 melanoma patients [stage I-II (n=10), stage III (n=14), stage IV (n=37), M1c (n=26) disease], and 50 healthy controls. It included 34 (56%) men, median age 53 years, range 16-88 years. Over half of the patients (54%) were in the metastatic stage and most of them (70%) had M1c. The plasma level of pretreatment blood coagulation tests including DD, F, APTT, INR levels, and PLT counts showed a statistically significant difference between the patient and the control group (P<0.001 for all, but P=0.049 for INR). The levels of INR, DD, F, and PLT counts were higher and APTT was lower in the melanoma group, whereas the PT and PTA levels did not show any significant difference. There was a significant association between PT, PTA, INR, and PLT levels and the age of the patient. Patients with node metastasis in M0 disease had higher levels of PTA and PLT counts (P=0.002 and 0.048, respectively) and lower levels of PT and INR (P=0.056 and 0.046, respectively). The M1c patients tended to have higher plasma F levels (437 vs. 297 mg/dl, P=0.055) than M1a and M1b patients. The 1-year survival rate for all patients was 70%. In association with distant metastasis, advanced metastatic stage (M1c), elevated lactate dehydrogenase, and erythrocyte sedimentation rate, only elevated plasma F levels had a significantly adverse effect on survival among the coagulation parameters (P=0.031). The 1-year survival rates for patients with high and normal F levels were 58 and 88%, respectively. In conclusion, changes in the coagulation-fibrinolytic system are often present in melanoma and elevation in the plasma F level is associated with decreased survival.

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Section: Discussionmentioning

confidence: 99%

Clinical and prognostic significance of coagulation assays in melanoma

et al. 2012

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“…Metastatic melanoma cells were recently found to have lower levels of maspin expression, compared to normal human epidermal melanocytes. We recently demonstrated that in two highly metastatic melanoma cell lines, PAR-1 inhibits maspin expression by promoting the phophorylation of p38, decreasing the recruitment of CBP/p300, as well as c-Jun and Ets-1 transcription factors, to the maspin promoter (13). This inhibition results in increased melanoma cell invasion.…”

Section: The Effect Of Thrombin/par-1 On Tumor Cellsmentioning

confidence: 99%

PAR-1 and Thrombin: The Ties That Bind the Microenvironment to Melanoma Metastasis

et al. 2011

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Progression of melanoma is dependent on cross-talk between tumor cells and the adjacent microenvironment. The thrombin receptor, Protease Activated Receptor-1 (PAR-1) plays a key role in exerting this function during melanoma progression. PAR-1 and its activating factors, which are expressed on tumor cells and the surrounding stroma, induce not only coagulation, but also cell signaling which promotes the metastatic phenotype. Several adhesion molecules, cytokines, growth factors and proteases have recently been identified as downstream targets of PAR-1 and have been shown to modulate interactions between tumor cells and the microenvironment in the process of melanoma growth and metastasis. Inhibition of these interactions by targeting PAR-1 could be utilized as a potential therapeutic modality for melanoma patients.

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“…For instance, its proteolytic activation by thrombin caused persistent activation of EGFR/ERK signaling, promoting thereafter breast carcinoma cell invasion [54] . Moreover, PAR-1 negatively regulated the expression of the Maspin tumor-suppressor gene contributing to the metastatic phenotype of melanoma [55] . It has been recently reported that metalloprotease-1 (MMP1) may function as a protease agonist of PAR-1 which then stimulates migration, invasion and angiogenesis in breast and ovarian malignancies [56,57] .…”

Section: Gpcrs Activated By Peptidesmentioning

confidence: 99%

GPCRs and cancer

Lappano

2012

Acta Pharmacol Sin

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G-protein-coupled receptors (GPCRs), which represent the largest gene family in the human genome, play a crucial role in multiple physiological functions as well as in tumor growth and metastasis. For instance, various molecules like hormones, lipids, peptides and neurotransmitters exert their biological effects by binding to these seven-transmembrane receptors coupled to heterotrimeric G-proteins, which are highly specialized transducers able to modulate diverse signaling pathways. Furthermore, numerous responses mediated by GPCRs are not dependent on a single biochemical route, but result from the integration of an intricate network of transduction cascades involved in many physiological activities and tumor development. This review highlights the emerging information on the various responses mediated by a selected choice of GPCRs and the molecular mechanisms by which these receptors exert a primary action in cancer progression. These findings provide a broad overview on the biological activity elicited by GPCRs in tumor cells and contribute to the identification of novel pharmacological approaches for cancer patients.

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

Cited by 45 publications

References 39 publications

Clinical and prognostic significance of coagulation assays in melanoma

Clinical and prognostic significance of coagulation assays in melanoma

PAR-1 and Thrombin: The Ties That Bind the Microenvironment to Melanoma Metastasis

GPCRs and cancer

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