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

Research Article

Tuula Salo¹  Inigo Martinez-Zubiaurre²  Cristiane Cavalcanti Jacobsen³  Jan-Olof Winberg³  Bente Mortensen³  Eli Berg³  Synnove Norvoll Magnussen³  Gunbjorg Svineng³  Lars Uhlin-Hansen⁴  Elin Hadler-Olsen⁴  Daniela Elena Costea⁵ 

[1] Cancer and Translational Research Medicine Unit, University of Oulu, Oulu, Finland;Medical Research Center, Oulu University Hospital, Oulu, Finland;Oral and Maxillofacial diseases, Clinicum, University of Helsinki, Helsinki, Finland;Helsinki University Hospital Helsinki, Helsinki, Finland;Department of Oral Diagnosis, Oral Pathology Division, Piracicaba Dental School, University of Campinas, SP-13414-903, Piracicaba, São Paulo, Brazil;Department of Clinical Medicine, Faculty of Health Sciences, UiT – The Arctic University of Norway, Tromsø, Norway;Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of Norway, N-9037, Tromsø, Norway;Department of Medical Biology, Faculty of Health Sciences, UiT – The Arctic University of Norway, N-9037, Tromsø, Norway;Diagnostic Clinic – Clinical Pathology, University Hospital of North Norway, Tromsø, Norway;Gade Laboratory for Pathology, Department of Clinical Medicine, Faculty of Medicine and Dentistry, University of Bergen, Bergen, Norway;Department of Pathology, Haukeland University Hospital, Bergen, Norway;

关键词: Urokinase plasminogen activator receptor (uPAR);    Urokinase receptor;    Transforming growth factor-beta1 (TGF-β1);    Plasminogen;    Plasmin;    Cancer;    Cell migration;    Urokinase;    Invasion;   

DOI  :  10.1186/s12885-017-3349-7

 received in 2016-10-28, accepted in 2017-05-12,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundUrokinase 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.MethodsMouse 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.ResultsWe 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.ConclusionsThese 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.

【 授权许可】

CC BY   
© The Author(s). 2017