Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis.
In: Oncogene, Jg. 34 (2015-01-16), Heft 3, S. 346-356
Online
academicJournal
Zugriff:
The membrane-anchored serine protease, matriptase, is consistently dysregulated in a range of human carcinomas, and high matriptase activity correlates with poor prognosis. Furthermore, matriptase is unique among tumor-associated proteases in that epithelial stem cell expression of the protease suffices to induce malignant transformation. Here, we use genetic epistasis analysis to identify proteinase-activated receptor (PAR)-2-dependent inflammatory signaling as an essential component of matriptase-mediated oncogenesis. In cell-based assays, matriptase was a potent activator of PAR-2, and PAR-2 activation by matriptase caused robust induction of nuclear factor (NF)κB through Gαi. Importantly, genetic elimination of PAR-2 from mice completely prevented matriptase-induced pre-malignant progression, including inflammatory cytokine production, inflammatory cell recruitment, epidermal hyperplasia and dermal fibrosis. Selective ablation of PAR-2 from bone marrow-derived cells did not prevent matriptase-driven pre-malignant progression, indicating that matriptase activates keratinocyte stem cell PAR-2 to elicit its pro-inflammatory and pro-tumorigenic effects. When combined with previous studies, our data suggest that dual induction of PAR-2-NFκB inflammatory signaling and PI3K-Akt-mTor survival/proliferative signaling underlies the transforming potential of matriptase and may contribute to pro-tumorigenic signaling in human epithelial carcinogenesis. [ABSTRACT FROM AUTHOR]
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Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis.
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Autor/in / Beteiligte Person: | Sales, K U ; Friis, S ; Konkel, J E ; Godiksen, S ; Hatakeyama, M ; Hansen, K K ; Rogatto, S R ; Szabo, R ; Vogel, L K ; Chen, W ; Gutkind, J S ; Bugge, T H |
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Zeitschrift: | Oncogene, Jg. 34 (2015-01-16), Heft 3, S. 346-356 |
Veröffentlichung: | 2015 |
Medientyp: | academicJournal |
ISSN: | 0950-9232 (print) |
DOI: | 10.1038/onc.2013.563 |
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