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Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis
- Source :
- Oncogene
- Publication Year :
- 2014
- Publisher :
- Springer Science and Business Media LLC, 2014.
-
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.
- Subjects :
- Keratinocytes
Cancer Research
Proteases
Skin Neoplasms
medicine.medical_treatment
Cell
GTP-Binding Protein alpha Subunits, Gi-Go
Biology
medicine.disease_cause
Article
Cell Line
Malignant transformation
Genetics
medicine
Animals
Humans
Receptor, PAR-2
Matriptase
Molecular Biology
Cells, Cultured
Mice, Knockout
Reverse Transcriptase Polymerase Chain Reaction
keratinocyte stem cells
Serine Endopeptidases
HEK 293 cells
NF-kappa B
Epithelial Cells
Immunohistochemistry
Molecular biology
Mice, Inbred C57BL
Cell Transformation, Neoplastic
HEK293 Cells
medicine.anatomical_structure
Cytokine
inflammation
Carcinoma, Squamous Cell
Disease Progression
ras Proteins
Cancer research
biology.protein
Cytokines
epithelial carcinogenesis
pericellular proteolysis
Stem cell
Carcinogenesis
Precancerous Conditions
Subjects
Details
- ISSN :
- 14765594 and 09509232
- Volume :
- 34
- Database :
- OpenAIRE
- Journal :
- Oncogene
- Accession number :
- edsair.doi.dedup.....ee5f565a9eb730a5cc25c54de0495024