Abstract
BackgroundThe urokinase plasminogen activator receptor (uPAR) is associated with poor prognosis in oral squamous cell carcinoma (OSCC), and increased expression of uPAR is often found at the invasive tumour front. The aim of the current study was to elucidate the role of uPAR in invasion and metastasis of OSCC, and the effects of various tumour microenvironments in these processes. Furthermore, we wanted to study whether the cells’ expression level of uPAR affected the activity of gelatinolytic enzymes.MethodsThe Plaur gene was both overexpressed and knocked-down in the murine OSCC cell line AT84. Tongue and skin tumours were established in syngeneic mice, and cells were also studied in an ex vivo leiomyoma invasion model. Soluble factors derived from leiomyoma tissue, as well as purified extracellular matrix (ECM) proteins, were assessed for their ability to affect uPAR expression, glycosylation and cleavage. Activity of gelatinolytic enzymes in the tissues were assessed by in situ zymography.ResultsWe found that increased levels of uPAR did not induce tumour invasion or metastasis. However, cells expressing low endogenous levels of uPAR in vitro up-regulated uPAR expression both in tongue, skin and leiomyoma tissue. Various ECM proteins had no effect on uPAR expression, while soluble factors originating from the leiomyoma tissue increased both the expression and glycosylation of uPAR, and possibly also affected the proteolytic processing of uPAR. Tumours with high levels of uPAR, as well as cells invading leiomyoma tissue with up-regulated uPAR expression, all displayed enhanced activity of gelatinolytic enzymes.ConclusionsAlthough high levels of uPAR are not sufficient to induce invasion and metastasis, the activity of gelatinolytic enzymes was increased. Furthermore, several tumour microenvironments have the capacity to induce up-regulation of uPAR expression, and soluble factors in the tumour microenvironment may have an important role in the regulation of posttranslational modification of uPAR.
Highlights
Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity [1,2], with a poor 5-year survival rate [2,3,4]
The plasminogen activation (PA) system consists of plasminogen which is the precursor of the active serine protease plasmin, its two activators (tissue-type plasminogen activator and Urokinase-type plasminogen activator (uPA)), urokinase plasminogen activator receptor (uPAR), as well as the inhibitors plasminogen activator inhibitor-1 (PAI-1) and PAI-2. uPA is secreted in its inactive pro-form, and is readily activated in a feed-back-loop by plasmin upon binding to uPAR. uPAR is a highly glycosylated protein consisting of three homologous domains (D1, D2, and D3) and is linked to the plasma membrane via a GPI-anchor [11]
Overexpression of uPAR in the murine AT84 cell line uPAR expression is often increased in oral squamous cell carcinoma (OSCC) at the invasive front [40], suggesting that it may have a role in invasion and metastasis
Summary
Oral squamous cell carcinoma (OSCC) is the most common malignancy of the oral cavity [1,2], with a poor 5-year survival rate [2,3,4]. Plasmin, uPA, trypsin, chymotrypsin, cathepsin G, elastase and some MMPs are all able to cleave uPAR in the linker region between D1 and D2 [14,15,16,17]. This disrupts the receptor’s ability to bind uPA [18] in what is thought to be a natural regulation of the uPA-mediated proteolytic activity [19]. The urokinase plasminogen activator receptor (uPAR) is associated with poor prognosis in oral squamous cell carcinoma (OSCC), and increased expression of uPAR is often found at the invasive tumour front. We wanted to study whether the cells’ expression level of uPAR affected the activity of gelatinolytic enzymes
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