Urokinase receptor promotes skin tumor formation by preventing epithelial cell activation of Notch1

Mazzieri, Roberta, Pietrogrande, Giovanni, Gerasi, Laura, Gandelli, Alessandro, Colombo, Piergiuseppe, Moi, Davide, Brombin, Chiara, Ambrosi, Alessandro, Danese, Silvio, Mignatti, Paolo, Blasi, Francesco and D'Alessio, Silvia (2015) Urokinase receptor promotes skin tumor formation by preventing epithelial cell activation of Notch1. Cancer Research, 75 22: 4895-4909. doi:10.1158/0008-5472.CAN-15-0378


Author Mazzieri, Roberta
Pietrogrande, Giovanni
Gerasi, Laura
Gandelli, Alessandro
Colombo, Piergiuseppe
Moi, Davide
Brombin, Chiara
Ambrosi, Alessandro
Danese, Silvio
Mignatti, Paolo
Blasi, Francesco
D'Alessio, Silvia
Title Urokinase receptor promotes skin tumor formation by preventing epithelial cell activation of Notch1
Journal name Cancer Research   Check publisher's open access policy
ISSN 0008-5472
1538-7445
Publication date 2015-11-15
Sub-type Article (original research)
DOI 10.1158/0008-5472.CAN-15-0378
Open Access Status Not Open Access
Volume 75
Issue 22
Start page 4895
End page 4909
Total pages 15
Place of publication Philadelphia, PA, United States
Publisher American Association for Cancer Research
Language eng
Formatted abstract
The urokinase-type plasminogen activator receptor (uPAR) has a well-established role in cancer progression, but it has been little studied at earlier stages of cancer initiation. Here, we show that uPAR deficiency in the mouse dramatically reduces susceptibility to the classical two-stage protocol of inflammatory skin carcinogenesis. uPAR genetic deficiency decreased papilloma formation and accelerated keratinocyte differentiation, effects mediated by Notch1 hyperactivation. Notably, Notch1 inhibition in uPAR-deficient mice rescued their susceptibility to skin carcinogenesis. Clinically, we found that human differentiated keratoacanthomas expressed low levels of uPAR and high levels of activated Notch1, with opposite effects in proliferating tumors, confirming the relevance of the observations in mice. Furthermore, we found that TACE-dependent activation of Notch1 in basal kerantinocytes was modulated by uPAR. Mechanistically, uPAR sequestered TACE within lipid rafts to prevent Notch1 activation, thereby promoting cell proliferation and tumor formation. Given that uPAR signaling is nonessential for normal epidermal homeostasis, our results argue that uPAR may present a promising disease-specific target for preventing skin cancer development.
Keyword Breast cancer cells
Epidermal stem cells
Plasminogen activator
Lipid rafts
Mesenchymal transition
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2016 Collection
UQ Diamantina Institute Publications
 
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