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
|Author:||Magnussen, Synnove Norvoll1; Hadler-Olsen, Elin1,2; Costea, Daniela Elena3,4;|
1Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of Norway
2Diagnostic Clinic – Clinical Pathology, University Hospital of North Norway
3Gade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine and Dentistry, University of Bergen
4Department of Pathology, Haukeland University Hospital
5Cancer and Translational Research Medicine Unit, University of Oulu
6Medical Research Center, Oulu University Hospital
7Oral and Maxillofacial diseases, Clinicum, University of Helsinki
8Helsinki University Hospital Helsinki
9Department of Oral Diagnosis, Oral Pathology Division, Piracicaba Dental School, University of Campinas
10Department of Clinical Medicine, Faculty of Health Sciences, UiT – The Arctic University of Norway
|Online Access:||PDF Full Text (PDF, 3.1 MB)|
|Persistent link:|| http://urn.fi/urn:nbn:fi-fe201707047629
|Publish Date:|| 2017-07-04
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.
|Type of Publication:||
A1 Journal article – refereed
|Field of Science:||
The work was funded by UiT- The Arctic University of Norway and grants from the Norwegian Regional Health Authorities (HelseNord and HelseVest).
© The Author(s). 2017. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.