MMP-1/PAR-1 signal transduction axis and its prognostic impact in esophageal squamous cell carcinoma

Abstract

The matrix metalloprotease-1 (MMP-1)/protease-activated receptor-1 (PAR-1) signal transduction axis plays an important role in tumorigenesis. To explore the expression and prognostic value of MMP-1 and PAR-1 in esophageal squamous cell carcinoma (ESCC), we evaluated the expression of two proteins in resected specimens from 85 patients with ESCC by immunohistochemistry. Sixty-two (72.9%) and 58 (68.2%) tumors were MMP-1- and PAR-1-positive, respectively, while no significant staining was observed in normal esophageal squamous epithelium. MMP-1 and PAR-1 overexpression was significantly associated with tumor node metastasis (TNM) stage and regional lymph node involvement. Patients with MMP-1- and PAR-1-positive tumors, respectively, had poorer disease-free survival (DFS) than those with negative ESCC (P = 0.002 and 0.003, respectively). Univariate analysis showed a significant relationship between TNM stage [hazard ratio (HR) = 2.836, 95% confidence interval (CI) = 1.866-4.308], regional lymph node involvement (HR = 2.955, 95%CI = 1.713-5.068), MMP-1 expression (HR = 2.669, 95%CI = 1.229-6.127), and PAR-1 expression (HR = 1.762, 95%CI = 1.156-2.883) and DFS. Multivariate analysis including the above four parameters identified TNM stage (HR = 2.035, 95%CI = 1.167-3.681), MMP-1 expression (HR = 2.109, 95%CI = 1.293-3.279), and PAR-1 expression (HR = 1.967, 95%CI = 1.256-2.881) as independent and significant prognostic factors for DFS. Our data suggest for the first time that MMP-1 and PAR-1 were both overexpressed in ESCC and are novel predictors of poor patient prognosis after curative resection. The MMP-1/PAR-1 signal transduction axis might be a new therapeutic target for future therapies tailored against ESCC.

Combined upregulation of matrix metalloproteinase-1 and proteinase-activated receptor-1 predicts unfavorable prognosis in human nasopharyngeal carcinoma

“…According to our data in this study, MMP-1 and PAR-1 were both overexpressed in NPC tissues, which is consistent with the previous studies of Ben Nasr et al19 and Zhu et al30 Interestingly, the expression levels of MMP-1 in the NPC specimens were significantly correlated with those of PAR-1, suggesting a regulatory relationship between MMP-1 and PAR-1. In addition, we found that MMP-1 and/or PAR-1 expression levels were all associated with aggressive tumor progression and poor overall survival of the NPC patients, which is also similar with the previous findings in other cancers 22–24. More importantly, the multivariate analyses here showed that the combined MMP-1 and PAR-1 overexpression was an independent prognostic factor for overall survival ( P = 0.001) in NPC patients, but the upregulation of MMP-1 and PAR-1 alone was, in each case, not an independent prognostic factors for this disease, suggesting the importance of the interaction between MMP-1 and PAR-1 in the clinical outcome of NPC patients.…”

“…PAR-1 expression has been similarly demonstrated to correlate with tumor progression both in vitro and in vivo. In light of the potential significance of MMP-1 and PAR-1 in the tumorigenesis and tumor progression of various cancers, accumulating studies22–24 have been performed to investigate the role of the MMP-1/PAR-1 axis in cancers. For example, the blockage of the MMP-1/PAR-1 interaction by a monoclonal antibody against PAR-1 has been shown to significantly reduce the migration ability of human mesenchymal stem cells 35.…”

“…Peng et al22 reported that the MMP-1/PAR-1 signal transduction axis might be a new therapeutic target for future therapies tailored against esophageal squamous cell carcinoma. Liao et al24 found that both the overexpression of MMP-1 and PAR-1 was significantly associated with poor prognosis in hepatocellular carcinoma.…”

“…Recently, a novel MMP-1 signaling axis (through activation of the protease-activated receptor [PAR]-1 to promote tumorigenesis and tumor invasion) has been identified in various cancers, such as breast cancer,20 epithelial ovarian cancer,21 esophageal squamous cell carcinoma,22 glioma,23 and hepatocellular carcinoma 24. The PARs are known as the cellular seven transmembrane G protein-coupled receptors (GPCRs) for thrombin 25.…”

Tumor MMP-1 Activates Endothelial PAR1 to Facilitate Vascular Intravasation and Metastatic Dissemination

“…also reported that the PAR1 pathway can be activated by conditioned medium containing MMP-1 secreted by tumor cells (38). Furthermore, in a number of recent clinical studies MMP-1 and PAR1 co-expression or co-localization in tumor tissues positively correlated with poor prognosis or unfavorable outcome for three different types of human carcinomas (39-41). …”