Cleavage of the urokinase receptor (uPAR) on oral cancer cells: regulation by transforming growth factor – β1 (TGF-β1) and potential effects on migration and invasion
Abstract Background Urokinase plasminogen activator (uPA) receptor (uPAR) is up-regulated at the invasive tumour front of human oral squamous cell carcinoma (OSCC), indicating a role for uPAR in tumour progression. We previously observed elevated expression of uPAR at the tumour-stroma interface in...
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| Format: | Article |
| Language: | English |
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BMC
2017-05-01
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| Series: | BMC Cancer |
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| Online Access: | http://link.springer.com/article/10.1186/s12885-017-3349-7 |
| _version_ | 1819022291247300608 |
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| author | Synnove Norvoll Magnussen Elin Hadler-Olsen Daniela Elena Costea Eli Berg Cristiane Cavalcanti Jacobsen Bente Mortensen Tuula Salo Inigo Martinez-Zubiaurre Jan-Olof Winberg Lars Uhlin-Hansen Gunbjorg Svineng |
| author_facet | Synnove Norvoll Magnussen Elin Hadler-Olsen Daniela Elena Costea Eli Berg Cristiane Cavalcanti Jacobsen Bente Mortensen Tuula Salo Inigo Martinez-Zubiaurre Jan-Olof Winberg Lars Uhlin-Hansen Gunbjorg Svineng |
| author_sort | Synnove Norvoll Magnussen |
| collection | DOAJ |
| description | Abstract Background Urokinase plasminogen activator (uPA) receptor (uPAR) is up-regulated at the invasive tumour front of human oral squamous cell carcinoma (OSCC), indicating a role for uPAR in tumour progression. We previously observed elevated expression of uPAR at the tumour-stroma interface in a mouse model for OSCC, which was associated with increased proteolytic activity. The tumour microenvironment regulated uPAR expression, as well as its glycosylation and cleavage. Both full-length- and cleaved uPAR (uPAR (II-III)) are involved in highly regulated processes such as cell signalling, proliferation, migration, stem cell mobilization and invasion. The aim of the current study was to analyse tumour associated factors and their effect on uPAR cleavage, and the potential implications for cell proliferation, migration and invasion. Methods Mouse uPAR was stably overexpressed in the mouse OSCC cell line AT84. The ratio of full-length versus cleaved uPAR as analysed by Western blotting and its regulation was assessed by addition of different protease inhibitors and transforming growth factor - β1 (TGF-β1). The role of uPAR cleavage in cell proliferation and migration was analysed using real-time cell analysis and invasion was assessed using the myoma invasion model. Results We found that when uPAR was overexpressed a proportion of the receptor was cleaved, thus the cells presented both full-length uPAR and uPAR (II-III). Cleavage was mainly performed by serine proteases and urokinase plasminogen activator (uPA) in particular. When the OSCC cells were stimulated with TGF-β1, the production of the uPA inhibitor PAI-1 was increased, resulting in a reduction of uPAR cleavage. By inhibiting cleavage of uPAR, cell migration was reduced, and by inhibiting uPA activity, invasion was reduced. We could also show that medium containing soluble uPAR (suPAR), and cleaved soluble uPAR (suPAR (II-III)), induced migration in OSCC cells with low endogenous levels of uPAR. Conclusions These results show that soluble factors in the tumour microenvironment, such as TGF-β1, PAI-1 and uPA, can influence the ratio of full length and uPAR (II-III) and thereby potentially effect cell migration and invasion. Resolving how uPAR cleavage is controlled is therefore vital for understanding how OSCC progresses and potentially provides new targets for therapy. |
| first_indexed | 2024-12-21T04:20:40Z |
| format | Article |
| id | doaj.art-0ddbb5a783ec4fe795e5088ad12c3dd1 |
| institution | Directory Open Access Journal |
| issn | 1471-2407 |
| language | English |
| last_indexed | 2024-12-21T04:20:40Z |
| publishDate | 2017-05-01 |
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| series | BMC Cancer |
| spelling | doaj.art-0ddbb5a783ec4fe795e5088ad12c3dd12022-12-21T19:16:11ZengBMCBMC Cancer1471-24072017-05-0117111610.1186/s12885-017-3349-7Cleavage of the urokinase receptor (uPAR) on oral cancer cells: regulation by transforming growth factor – β1 (TGF-β1) and potential effects on migration and invasionSynnove Norvoll Magnussen0Elin Hadler-Olsen1Daniela Elena Costea2Eli Berg3Cristiane Cavalcanti Jacobsen4Bente Mortensen5Tuula Salo6Inigo Martinez-Zubiaurre7Jan-Olof Winberg8Lars Uhlin-Hansen9Gunbjorg Svineng10Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayDepartment of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayGade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine and Dentistry, University of BergenDepartment of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayDepartment of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayDepartment of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayCancer and Translational Research Medicine Unit, University of OuluDepartment of Clinical Medicine, Faculty of Health Sciences, UiT – The Arctic University of NorwayDepartment of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayDepartment of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayDepartment of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of NorwayAbstract Background Urokinase plasminogen activator (uPA) receptor (uPAR) is up-regulated at the invasive tumour front of human oral squamous cell carcinoma (OSCC), indicating a role for uPAR in tumour progression. We previously observed elevated expression of uPAR at the tumour-stroma interface in a mouse model for OSCC, which was associated with increased proteolytic activity. The tumour microenvironment regulated uPAR expression, as well as its glycosylation and cleavage. Both full-length- and cleaved uPAR (uPAR (II-III)) are involved in highly regulated processes such as cell signalling, proliferation, migration, stem cell mobilization and invasion. The aim of the current study was to analyse tumour associated factors and their effect on uPAR cleavage, and the potential implications for cell proliferation, migration and invasion. Methods Mouse uPAR was stably overexpressed in the mouse OSCC cell line AT84. The ratio of full-length versus cleaved uPAR as analysed by Western blotting and its regulation was assessed by addition of different protease inhibitors and transforming growth factor - β1 (TGF-β1). The role of uPAR cleavage in cell proliferation and migration was analysed using real-time cell analysis and invasion was assessed using the myoma invasion model. Results We found that when uPAR was overexpressed a proportion of the receptor was cleaved, thus the cells presented both full-length uPAR and uPAR (II-III). Cleavage was mainly performed by serine proteases and urokinase plasminogen activator (uPA) in particular. When the OSCC cells were stimulated with TGF-β1, the production of the uPA inhibitor PAI-1 was increased, resulting in a reduction of uPAR cleavage. By inhibiting cleavage of uPAR, cell migration was reduced, and by inhibiting uPA activity, invasion was reduced. We could also show that medium containing soluble uPAR (suPAR), and cleaved soluble uPAR (suPAR (II-III)), induced migration in OSCC cells with low endogenous levels of uPAR. Conclusions These results show that soluble factors in the tumour microenvironment, such as TGF-β1, PAI-1 and uPA, can influence the ratio of full length and uPAR (II-III) and thereby potentially effect cell migration and invasion. Resolving how uPAR cleavage is controlled is therefore vital for understanding how OSCC progresses and potentially provides new targets for therapy.http://link.springer.com/article/10.1186/s12885-017-3349-7Urokinase plasminogen activator receptor (uPAR)Urokinase receptorTransforming growth factor-beta1 (TGF-β1)PlasminogenPlasminCancer |
| spellingShingle | Synnove Norvoll Magnussen Elin Hadler-Olsen Daniela Elena Costea Eli Berg Cristiane Cavalcanti Jacobsen Bente Mortensen Tuula Salo Inigo Martinez-Zubiaurre Jan-Olof Winberg Lars Uhlin-Hansen Gunbjorg Svineng Cleavage of the urokinase receptor (uPAR) on oral cancer cells: regulation by transforming growth factor – β1 (TGF-β1) and potential effects on migration and invasion BMC Cancer Urokinase plasminogen activator receptor (uPAR) Urokinase receptor Transforming growth factor-beta1 (TGF-β1) Plasminogen Plasmin Cancer |
| title | Cleavage of the urokinase receptor (uPAR) on oral cancer cells: regulation by transforming growth factor – β1 (TGF-β1) and potential effects on migration and invasion |
| title_full | Cleavage of the urokinase receptor (uPAR) on oral cancer cells: regulation by transforming growth factor – β1 (TGF-β1) and potential effects on migration and invasion |
| title_fullStr | Cleavage of the urokinase receptor (uPAR) on oral cancer cells: regulation by transforming growth factor – β1 (TGF-β1) and potential effects on migration and invasion |
| title_full_unstemmed | Cleavage of the urokinase receptor (uPAR) on oral cancer cells: regulation by transforming growth factor – β1 (TGF-β1) and potential effects on migration and invasion |
| title_short | Cleavage of the urokinase receptor (uPAR) on oral cancer cells: regulation by transforming growth factor – β1 (TGF-β1) and potential effects on migration and invasion |
| title_sort | cleavage of the urokinase receptor upar on oral cancer cells regulation by transforming growth factor β1 tgf β1 and potential effects on migration and invasion |
| topic | Urokinase plasminogen activator receptor (uPAR) Urokinase receptor Transforming growth factor-beta1 (TGF-β1) Plasminogen Plasmin Cancer |
| url | http://link.springer.com/article/10.1186/s12885-017-3349-7 |
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