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 percent) and 58 (68.2 percent) 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 percent confidence interval (CI) = 1.866-4.308], regional lymph node involvement (HR = 2.955, 95 percentCI = 1.713-5.068), MMP-1 expression (HR = 2.669, 95 percentCI = 1.229-6.127), and PAR-1 expression (HR = 1.762, 95 percentCI = 1.156-2.883) and DFS. Multivariate analysis including the above four parameters identified TNM stage (HR = 2.035, 95 percentCI = 1.167-3.681), MMP-1 expression (HR = 2.109, 95 percentCI = 1.293-3.279), and PAR-1 expression (HR = 1.967, 95 percentCI = 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.