Abstract
BackgroundThe urokinase plasminogen activating system (uPAS) is implicated in neoplastic progression and high tissue levels of uPAS components correlate with a poor prognosis in different human cancers. Despite that, relative few studies are available on the expression and function of the uPAS components in human seminomas. In the present study we characterized the expression of the urokinase plasminogen activator (uPA), its cognate receptor (uPAR) and the uPA inhibitors PAI-1 and PAI-2 in normal human testis and seminomas.MethodsThe expression of the above genes was evaluated by means of quantitative RT-PCR, western blot, zymographic analysis and immunohistochemistry.ResultsQuantitative RT-PCR analysis of 14 seminomas demonstrated that uPA and uPAR mRNAs were, with respect to control tissues, increased in tumor tissues by 3.80 ± 0.74 (p < 0.01) and 6.25 ± 1.18 (p < 0.01) fold, respectively. On the other hand, PAI-1 mRNA level was unchanged (1.02 ± 0.24 fold), while that of PAI-2 was significantly reduced to 0.34 ± 0.18 (p < 0.01) fold. Western blot experiments performed with protein extracts of three seminomas and normal tissues from the same patients showed that uPA protein levels were low or undetectable in normal tissues and induced in tumor tissues. On the same samples, zymographic analysis demonstrated increased uPA activity in tumor tissue extracts. Western blot experiments showed that also the uPAR protein was increased in tumor tissues by 1.83 ± 0.15 fold (p < 0.01). The increased expression of uPA and uPAR was further confirmed by immunohistochemical staining performed in 10 seminomas and autologous uninvolved peritumoral tissues. Finally, variation in the mRNA level of PAI-1 significantly correlated with tumor size.ConclusionsWe demonstrated the increased expression of uPA and uPAR in human seminomas with respect to normal testis tissues, which may be relevant in testicular cancer progression.
Highlights
The urokinase plasminogen activating system is implicated in neoplastic progression and high tissue levels of uPAS components correlate with a poor prognosis in different human cancers
We first evaluated the mRNA levels of the different components of the urokinase plasminogen activating system in 14 seminoma tissues in comparison to those observed in 6 normal testicular tissues
Quantitative RTPCR analysis showed significant (p < 0.01) increases for urokinase plasminogen activator (uPA) mRNA by 3.80 ± 0.74 fold, and uPA receptor (uPAR) mRNA by 6.25 ± 1.18 fold in tumor tissues with respect to normal tissues
Summary
The urokinase plasminogen activating system (uPAS) is implicated in neoplastic progression and high tissue levels of uPAS components correlate with a poor prognosis in different human cancers. It has been proposed that high levels of PAI-1 may promote cancer progression in several ways, that is by inhibiting cell adhesions, stimulating cancer cell motility, promoting tumor angiogenesis and preventing an excessive ECM proteolysis by plasmin that could prevent cellular migration [8,10,11,19,20,21] In view of their prognostic value, both uPA and PAI-1 are candidate molecular markers for clinical use in patients with breast cancer [8,11]. The involvement of uPAS at multiple steps during the neoplastic evolution represents an attractive target for anti-cancer therapy, and a number of studies aimed either to inhibit uPA expression, catalytic activity or to prevent its binding to uPAR have been performed with success on animals, while the results of trials in human cancers are awaited [11,22,26]
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