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Oncogene. 2015 Jan 15;34(3):346-56. doi: 10.1038/onc.2013.563. Epub 2014 Jan 27.

Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis.

Author information

1
1] Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA [2] Clinical Research Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
2
1] Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA [2] Department of Cellular and Molecular Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
3
Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
4
1] Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA [2] Department of Cellular and Molecular Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark [3] Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark.
5
1] Department of Urology, Faculty of Medicine, Sao Paulo State University (UNESP), Botucatu, Sao Paulo, Brazil [2] AC Camargo Cancer Center, Sao Paulo, Brazil.
6
Department of Cellular and Molecular Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.

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.

PMID:
24469043
PMCID:
PMC4112178
DOI:
10.1038/onc.2013.563
[Indexed for MEDLINE]
Free PMC Article

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