Urokinase receptor promotes ovarian cancer cell dissemination through its 84-95 sequence
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Katia Bifulco1, Giuseppina Votta2, Vincenzo Ingangi1, Gioconda Di Carluccio1, Domenica Rea1, Simona Losito3, Nunzia Montuori 4, Pia Ragno5, Maria Patrizia Stoppelli2, Claudio Arra1,* and Maria Vincenza Carriero1,*
1 Department of Experimental Oncology Unit, IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale”, Naples, Italy
2 Department of Experimental Pathology Unit, IRCCS Istituto Nazionale Tumori “Fondazione G. Pascale”, Naples, Italy
3 Institute of Genetics and Biophysics “Adriano Buzzati-Traverso”, National Research Council, Naples, Italy
4 Department of Translational Medical Sciences,‘‘Federico II’’ University, Naples, Italy
5 Department of Chemistry and Biology, University of Salerno, Fisciano (Salerno), Italy.
* These authors contributed equally
Maria Vincenza Carriero, email:
Keywords: Urokinase Receptor, Ovarian cancer, Cell Invasion
Received: February 21, 2014 Accepted: April 30, 2014 Published: May 1, 2014
The clinical relevance of the urokinase receptor (uPAR) as a prognostic marker in ovarian cancer is well documented. We have shown that the uPAR sequence corresponding to 84-95 residues, linking D1 and D2 domains (uPAR84-95), drives cell migration and angiogenesis in a protease-independent manner. This study is aimed at defining the contribution of uPAR84-95 sequence to invasion of ovarian cancer cells. Now, we provide evidence that the ability of uPAR-expressing ovarian cancer cells to cross extra-cellular matrix and mesothelial monolayers is prevented by specific inhibitors of PAR84-95 sequence. To specifically investigate uPAR84-95 function, uPAR-negative CHO-K1 cells were stably transfected with cDNAs coding for uPAR D2 and D3 regions and exposing (uPARD2D3) or lacking (uPAR∆D2D3) the 84–95 sequence. CHO-K1/D2D3 cells were able to cross matrigel, mesothelial and endothelial monolayers more efficiently than CHO-K1/∆D2D3 cells, which behave as CHO-K1 control cells. When orthotopically implanted in nude mice, tumor nodules generated by CHO-K1/D2D3 cells spreading to peritoneal cavity were more numerous as compared to CHO-K1/∆D2D3 cells. Ovarian tumor size and intra-tumoral microvessel density were significantly reduced in the absence of uPAR84-95. Our results indicate that cell associated uPAR promotes growth and abdominal dissemination of ovarian cancer cells mainly through its uPAR84-95 sequence.
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