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uPAR promotes tumor-like biologic behaviors of fibroblast-like synoviocytes through PI3K/Akt signaling pathway in patients with rheumatoid arthritis

Cellular & Molecular Immunology volume 15, pages 171–181 (2018)Cite this article

Abstract

Urokinase-type plasminogen activator receptor (uPAR), is a multifunctional receptor on cell surface, widely present in endothelial cells, fibroblasts, and a variety of malignant cells. Current studies have suggested that uPAR overexpressed on synovial tissues or in synovial fluid or plasma in patients with rheumatoid arthritis (RA). However, there are limited researches regarding the role of uPAR on fibroblast-like synoviocytes of rheumatoid arthritis (RA-FLSs) and its underlying mechanisms. Here, our studies show that the expression of uPAR protein was significantly higher in fibroblast-like synoviocytes (FLSs) from RA than those from osteoarthritis or traumatic injury patients. uPAR gene silencing significantly inhibited RA-FLSs cell proliferation, restrained cell transformation from the G0/G1 phase to S phase, aggravated cell apoptosis, interfered with RA-FLSs cell migration and invasion, and reduced activation of the PI3K/Akt signaling pathway, which may be associated with β1-integrin. Cell supernatants from uPAR gene-silenced RA-FLSs markedly inhibited the migration and tubule formation ability of the HUVECs (a human endothelial cell line). Therefore, we demonstrate that uPAR changes the biological characteristics of RA-FLSs, and affects neoangiogenesis of synovial tissues in patients with RA. All of these may be associated with the β1-integrin/PI3K/Akt signaling pathway. These results imply that targeting uPAR and its downstream signal pathway may provide therapeutic effects in RA.

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Acknowledgements

This work was supported in part by the grants from Science and Technology Planning Project of Guangdong Province, China (2012B031800363); Science and Technology Program of Guangzhou, China (Special Project on the Integration of Industry, Education and Research); Developing Program of the Major Research Plan of the National Natural Science Foundation of Guangdong, China (2014A030308005); National Natural Science Foundation of China (81671611); and Major National developing program of the national level in Higher Education of Guangdong, China (Natural Science).

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  1. Yan Liu and Yun Feng Pan: These authors contribute equally to this work.

Authors and Affiliations

  1. Division of Rheumatology, Department of Internal Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China

    Yan Liu, Yun Feng Pan, Lin-kai Fang, Xing-hua Guo, Bi-yao Mo, Meng-ru Yang & Fang Liu

  2. Department of Clinical Immunology, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China

    Yan Liu, Yun Feng Pan, You-qiu Xue & Song Guo Zheng

  3. Division of Rheumatology, Department of Internal Medicine, The Second People’s Hospital of Guangdong Province, Guangzhou, 510310, China

    Xin Guo & Meng Liu

  4. Division of Neurology, Department of Internal Medicine, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510630, China

    Yun-ting Wu

  5. Division of Rheumatology, Department of Medicine, Penn State Milton S. Hershey Medical Center, Hershey, 17033, PA, USA

    Nancy Olsen & Song Guo Zheng

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  1. Yan Liu
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Correspondence to Yun Feng Pan or Song Guo Zheng.

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Liu, Y., Pan, Y., Xue, Yq. et al. uPAR promotes tumor-like biologic behaviors of fibroblast-like synoviocytes through PI3K/Akt signaling pathway in patients with rheumatoid arthritis. Cell Mol Immunol 15, 171–181 (2018). https://doi.org/10.1038/cmi.2016.60

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