Downregulation of uPAR promotes urokinase translocation into the nucleus and epithelial to mesenchymal transition in neuroblastoma

Semina, E.V.; Rubina, K.A.; Shmakova, A.A.; Rysenkova, K.D.; Klimovich, P.S.; Aleksanrushkina, N.A.; Sysoeva, V.Y.; Karagyaur, M.N.; Tkachuk, V.A.

Авторы: Semina E.V., Rubina K.A., Shmakova A.A., Rysenkova K.D., Klimovich P.S., Aleksanrushkina N.A., Sysoeva V.Yu, Karagyaur M.N., Tkachuk V.A.
Журнал: Journal of Cellular Physiology
Год издания: 2020
Издательство: John Wiley & Sons Inc.
Местоположение издательства: United States
Первая страница: e1
Последняя страница: 19
DOI: 10.1002/jcp.29555
Аннотация: The urokinase system is involved in a variety of physiological processes such as fibrinolysis, matrix remodeling, wound healing and regeneration. Upon binding to its cognate receptor uPAR, uPA catalyzes the conversion of plasminogen to plasmin and the activation of matrix metalloproteases. Apart from this, uPA-uPAR interaction can lead to the activation of transcription factors, MAPK signaling pathways and RTK cascades. Elevated expression of uPA and uPAR is markedly associated with cancer progression and metastasis and correlates with a poor prognosis in clinics. Targeting the urokinase system has proved to be effective in experimental models in vitro and in vivo, however in clinics the inhibition of the uPA/uPAR system has fallen short of expectations, suggesting that the question of functional relevance of uPA/uPAR system is far from being moot. Recently, using CRISPR/Cas9 technology, we have shown that uPAR knockout decreases the proliferation of neuroblastoma Neuro2a cells in vitro. In the present study we demonstrate that uPAR expression is essential for maintaining the epithelial phenotype in Neuro2a cells and that uPAR silencing promotes epithelial-mesenchymal transition (EMT) and increased cell migration. Accordingly, uPAR knockout results in the downregulation of epithelial markers (E-cadherin, occludin and claudin-5) and in the increase of mesenchymal markers (N-cadherin, α-SMA and interleukin-6). In search of the molecular mechanism underlying these changes, we identified uPA as a key component. Two key insights emerged as a result of this work: in the absence of uPAR, uPA is translocated into the nucleus where it is presumably involved in the activation of transcription factors (NF-kβ and Snail) resulting in EMT. In uPAR-expressing cells, uPAR functions as a uPA “trap” that binds uPA on the cell surface and promotes controlled uPA internalization and degradation in lysosomes.
Добавил в систему: Семина Екатерина Владимировна

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