Abstract
BackgroundMembers 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.MethodsThe 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.ResultsElevated 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.ConclusionOur 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.
Highlights
Members of the urokinase-type plasminogen activator system are up-regulated in various solid malignant tumors
MRNA and their association with clinical and histomorphological parameters The expression of urokinase-type plasminogen activator (uPA) and PAI-1 mRNA was determined in 78 cases, and the expression of uPAR-wt and uPAR-del4/5 mRNA was determined in 77 and 76 soft-tissue sarcoma (STS) samples, respectively (Table 1)
All factors displayed a strong correlation with each other with rsvalues of approximately 0.80; uPA mRNA values significantly correlated with PAI-1, with uPAR-wt and with uPAR-del4/5 mRNA levels
Summary
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. The mRNA expression of uPA system components has not yet been comprehensively investigated in STS patients. High antigen levels of uPA and/or PAI-1 protein in tumor tissue extracts are strong predictors of poor prognosis in patients afflicted with different types of solid malignant tumors including sarcomas [10,11]. High uPAR levels are associated with poor prognosis in various cancer types, the prognostic impact of uPAR expression is not as pronounced as that of uPA and PAI-1 [12,13]. The expression of a mRNA splice variant of wild-type uPAR (uPAR-wt) lacking exons 4 and 5 (uPAR-del4/5) has been demonstrated to be a highly sensitive, independent prognostic marker in breast cancer patients [14,15,16]
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