uPA/PAI-1 expression and uPA promoter methylation in meningiomas

The extent of resection and the intrinsic biological aggressiveness of the tumor have been repeatedly identified as the primary determinants of meningioma recurrence. Invasive growth limits the resectability of meningiomas. Tumor invasion is mediated by matrix metalloproteases and their inhibitors such as uPA and PAI-1. In some cancers uPA expression is controlled in part by promoter methylation. In the work reported in this paper we investigated the role of uPA/PAI-1 expression and methylation of the uPA promoter in meningiomas. Sixty-five tumor tissue samples (WHO grade I: 26, grade II: 27, grade III: 12) from 58 patients were analyzed for uPA and PAI-1 protein content using a commercially available ELISA kit. For uPA promoter methylation analysis, a 365-bp promoter fragment was amplified by PCR after bisulfite treatment and subjected to a methylation-sensitive restriction digest with AciI. Pertinent clinical data were retrieved from the patients' charts. uPA and PAI-1 protein expression correlated significantly with WHO grade (uPA: P < 0.033, PAI-1: P < 0.001). High (>6 ng/ml = median) PAI-1 levels were seen more frequently in tumors with brain invasion (P = 0.006) and proved a significant predictor of the patients' prognosis (Kaplan-Meier estimates of progression-free survival: P = 0.004). Increased methylation of the uPA promoter was found to correlate significantly with lower levels of uPA expression. Our data suggest PAI-1 (and possibly to a lesser degree uPA) as potential prognostic markers in meningiomas. uPA expression in meningiomas might, in part, be controlled by promoter methylation.