1. Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis.
- Author
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Sales KU, Friis S, Konkel JE, Godiksen S, Hatakeyama M, Hansen KK, Rogatto SR, Szabo R, Vogel LK, Chen W, Gutkind JS, and Bugge TH
- Subjects
- Animals, Carcinoma, Squamous Cell genetics, Carcinoma, Squamous Cell metabolism, Cell Line, Cell Transformation, Neoplastic genetics, Cells, Cultured, Cytokines genetics, Cytokines metabolism, Disease Progression, Epithelial Cells pathology, GTP-Binding Protein alpha Subunits, Gi-Go genetics, GTP-Binding Protein alpha Subunits, Gi-Go metabolism, HEK293 Cells, Humans, Immunohistochemistry, Keratinocytes metabolism, Mice, Inbred C57BL, Mice, Knockout, NF-kappa B genetics, NF-kappa B metabolism, Precancerous Conditions genetics, Precancerous Conditions metabolism, Precancerous Conditions pathology, Receptor, PAR-2 genetics, Reverse Transcriptase Polymerase Chain Reaction, Serine Endopeptidases genetics, Skin Neoplasms genetics, Skin Neoplasms metabolism, ras Proteins genetics, Cell Transformation, Neoplastic metabolism, Epithelial Cells metabolism, Receptor, PAR-2 metabolism, Serine Endopeptidases metabolism, ras Proteins metabolism
- Abstract
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.
- Published
- 2015
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