Upregulation of matrix metalloproteinase-1 and proteinase-activated receptor-1 promotes the progression of human gliomas

Matrix metalloproteinases (MMPs) have been proposed to be involved in remodeling the tumor-stromal microenvironment. The protease-activated receptors (PARs) are the latest MMP targets. Recent studies have revealed that stromal-derived MMP-1 acts as a signaling molecule by cleaving PAR1 to cause tumor migration and invasion of various cancers. However, the involvement of MMP-1/PAR1 signaling pathway in the progression and prognosis of human gliomas remains to be identified. Immunohistochemical staining was performed to detect the expression patterns of MMP-1 and PAR1 in biopsies from 108 patients with primary gliomas. Kaplan-Meier survival and Cox regression analyzes were performed to evaluate the prognosis of patients. Immunostaining revealed MMP-1 to be expressed in 83.3% (90/108) and PAR1 in 76.9% (83/108) of the biopsies. PAR1 expression was significantly correlated with that of MMP-1 (r = 0.786, p<0.0001). The total IHC scores for MMP-1 and PAR1 were significantly higher in high-grade tumors than in low-grade tumors (both p = 0.001). In addition, patients with high MMP-1 and high PAR1 expression have lower Karnofsky performance scale (KPS) scores than patients with low MMP-1 and low PAR1 expression (both p = 0.008). Moreover, MMP-1 and PAR1 expression was shown to be a strong prognostic marker for decreased overall survival (p = 0.002 and 0.003, respectively). Furthermore, Cox multi-factor analysis showed that KPS (p = 0.008), WHO grade (p = 0.006), MMP-1 (p = 0.006), and PAR1 (p = 0.008) were independent prognostic factors for human gliomas. Our results suggest that in gliomas, the upregulation of MMP-1 and PAR1 correlates with histological malignancy grade and clinical outcome. Also, MMP-1 and PAR1 immunostaining supplements the current histological grading by offering additional prognostic and predictive information.