Prognostic Value of Matrix Metalloproteinase-1/ Proteinase-Activated Receptor-1 Signaling Axis in Hepatocellular Carcinoma

Abstract

Matrix metalloproteinase-1 (MMP-1) is proposed to be involved in both tumor cell invasion and metastasis. MMP-1 proteolytically activates protease activated receptor-1 (PAR-1), which also plays an important role in tumor development and progression. However, it is currently unknown whether MMP-1 activation of PAR-1 has relevance to the progression of hepatocellular carcinoma (HCC). To address this problem, we investigate the clinicopathological and prognostic value of MMP-1/PAR-1 signaling axis in HCC. Immunohistochemistry assay was used to determine the expression of MMP-1 and PAR-1 proteins in normal and HCC tissues. The correlations of MMP-1 and PAR-1 expression with clinicopathological parameters were assessed by Chi-squared test. Patient survival and their differences were determined by Kaplan-Meier method and log-rank test. Cox regression was adopted for multivariate analysis of prognostic factors. MMP-1 and PAR-1 immunoreactivities were negative or low in normal liver tissues, but high in HCC tissues. PAR-1 expression was significantly correlated with that of MMP-1 (r = 0.896, p < 0.0001). The overexpression of MMP-1 and PAR-1 was significantly associated with recurrence, TNM staging and portal vein invasion of HCC. Patients with high MMP-1 and PAR-1 expression had significantly poorer overall survival (OS) (both P < 0.001) and disease-free survival (DFS) (both P < 0.001) when compared with patients with the low expression of MMP-1 and PAR-1. On multivariate analysis, MMP-1 and PAR-1 expression patterns were found to be independent prognostic factors for OS (both P < 0.001) and DFS (both P < 0.001). Our results suggest for the first time that the MMP-1/PAR-1 signaling axis might be applied as a novel marker for the prediction of recurrence and metastasis potency and a significant indicator of poor prognosis for patients with HCC.