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Tumour Microenvironments Induce Expression of Urokinase Plasminogen Activator Receptor (uPAR) and Concomitant Activation of Gelatinolytic Enzymes

BACKGROUND: 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. The aim of the current study was to elucidate the role of uPAR in invasion and metas...

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Autores principales: Magnussen, Synnøve, Hadler-Olsen, Elin, Latysheva, Nadezhda, Pirila, Emma, Steigen, Sonja E., Hanes, Robert, Salo, Tuula, Winberg, Jan-Olof, Uhlin-Hansen, Lars, Svineng, Gunbjørg
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2014
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144900/
https://www.ncbi.nlm.nih.gov/pubmed/25157856
http://dx.doi.org/10.1371/journal.pone.0105929
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author Magnussen, Synnøve
Hadler-Olsen, Elin
Latysheva, Nadezhda
Pirila, Emma
Steigen, Sonja E.
Hanes, Robert
Salo, Tuula
Winberg, Jan-Olof
Uhlin-Hansen, Lars
Svineng, Gunbjørg
author_facet Magnussen, Synnøve
Hadler-Olsen, Elin
Latysheva, Nadezhda
Pirila, Emma
Steigen, Sonja E.
Hanes, Robert
Salo, Tuula
Winberg, Jan-Olof
Uhlin-Hansen, Lars
Svineng, Gunbjørg
author_sort Magnussen, Synnøve
collection PubMed
description BACKGROUND: 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. 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. METHODS: The 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. RESULTS: We 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. CONCLUSIONS: Although 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.
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spelling pubmed-41449002014-08-29 Tumour Microenvironments Induce Expression of Urokinase Plasminogen Activator Receptor (uPAR) and Concomitant Activation of Gelatinolytic Enzymes Magnussen, Synnøve Hadler-Olsen, Elin Latysheva, Nadezhda Pirila, Emma Steigen, Sonja E. Hanes, Robert Salo, Tuula Winberg, Jan-Olof Uhlin-Hansen, Lars Svineng, Gunbjørg PLoS One Research Article BACKGROUND: 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. 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. METHODS: The 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. RESULTS: We 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. CONCLUSIONS: Although 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. Public Library of Science 2014-08-26 /pmc/articles/PMC4144900/ /pubmed/25157856 http://dx.doi.org/10.1371/journal.pone.0105929 Text en © 2014 Magnussen et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Magnussen, Synnøve
Hadler-Olsen, Elin
Latysheva, Nadezhda
Pirila, Emma
Steigen, Sonja E.
Hanes, Robert
Salo, Tuula
Winberg, Jan-Olof
Uhlin-Hansen, Lars
Svineng, Gunbjørg
Tumour Microenvironments Induce Expression of Urokinase Plasminogen Activator Receptor (uPAR) and Concomitant Activation of Gelatinolytic Enzymes
title Tumour Microenvironments Induce Expression of Urokinase Plasminogen Activator Receptor (uPAR) and Concomitant Activation of Gelatinolytic Enzymes
title_full Tumour Microenvironments Induce Expression of Urokinase Plasminogen Activator Receptor (uPAR) and Concomitant Activation of Gelatinolytic Enzymes
title_fullStr Tumour Microenvironments Induce Expression of Urokinase Plasminogen Activator Receptor (uPAR) and Concomitant Activation of Gelatinolytic Enzymes
title_full_unstemmed Tumour Microenvironments Induce Expression of Urokinase Plasminogen Activator Receptor (uPAR) and Concomitant Activation of Gelatinolytic Enzymes
title_short Tumour Microenvironments Induce Expression of Urokinase Plasminogen Activator Receptor (uPAR) and Concomitant Activation of Gelatinolytic Enzymes
title_sort tumour microenvironments induce expression of urokinase plasminogen activator receptor (upar) and concomitant activation of gelatinolytic enzymes
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4144900/
https://www.ncbi.nlm.nih.gov/pubmed/25157856
http://dx.doi.org/10.1371/journal.pone.0105929
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