Combined mRNA expression levels of members of the urokinase plasminogen activator (uPA) system correlate with disease-associated survival of soft-tissue sarcoma patients

Abstract

Background: Members of the urokinase-type plasminogen activator (uPA) system are up-regulated in various solid malignant tumors. High antigen levels of uPA, its inhibitor PAI-1 and its receptor uPAR have recently been shown to be associated with poor prognosis in soft-tissue sarcoma (STS) patients. However, the mRNA expression of uPA system components has not yet been comprehensively investigated in STS patients.

Methods: The mRNA expression level of uPA, PAI-1, uPAR and an uPAR splice variant, uPAR-del4/5, was analyzed in tumor tissue from 78 STS patients by quantitative PCR.

Results: Elevated mRNA expression levels of PAI-1 and uPAR-del4/5 were significantly associated with clinical parameters such as histological subtype (P = 0.037 and P < 0.001, respectively) and higher tumor grade (P = 0.017 and P = 0.003, respectively). In addition, high uPAR-del4/5 mRNA values were significantly related to higher tumor stage of STS patients (P = 0.031). On the other hand, mRNA expression of uPA system components was not significantly associated with patients' survival. However, in STS patients with complete tumor resection (R0), high PAI-1 and uPAR-del4/5 mRNA levels were associated with a distinctly increased risk of tumor-related death (RR = 6.55, P = 0.054 and RR = 6.00, P = 0.088, respectively). Strikingly, R0 patients with both high PAI-1 and uPAR-del4/5 mRNA expression levels showed a significant, 19-fold increased risk of tumor-related death (P = 0.044) compared to the low expression group.

Conclusion: Our results suggest that PAI-1 and uPAR-del4/5 mRNA levels may add prognostic information in STS patients with R0 status and distinguish a subgroup of R0 patients with low PAI-1 and/or low uPAR-del4/5 values who have a better outcome compared to patients with high marker levels.

Figure 1

Multivariate Cox regression analysis for the association of combined PAI-1/uPAR-del4/5 mRNA values with disease-associated survival in the subgroup of STS patients with complete tumor resection (R0). For each, the PAI-1 and the uPAR-del4/5 mRNA level, the 33% percentile of the relative expression ratio was used as cut-off point. Group 1 (n = 13), low expression levels of PAI-1/uPAR-del4/5 mRNA; group 2 (n = 8), one of the mRNA values was either low or high; group 3 (n = 30), high expression levels of PAI-1/uPAR-del4/5 mRNA. R0 patients of group 3 (high expression of PAI-1/uPAR-del4/5 mRNA) showed a 19-fold increased risk of tumor-related death (RR = 19.1, 95%CI = 1.1-335.3, P = 0.044) compared to group 1 with low expression of PAI-1/uPAR-del4/5 mRNA.