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http://acervodigital.unesp.br/handle/11449/128404
- Title:
- Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis
- Natl Inst Dent &Craniofacial Res
- Univ Copenhagen
- Universidade Estadual Paulista (UNESP)
- AC Camargo Canc Ctr
- 0950-9232
- NIDCR Intramural Research Program
- Augustinus Foundation, Kobmand Kristian Kjaer og hustrus Foundation
- Kjaer-Foundation
- Dagmar Marshalls Foundation
- Snedkermester Sophus Jacobsen og Hustru Astrid Jacobsens Foundation
- Grosserer Valdemar Foersom og Hustru Thyra Foersoms Foundation
- Fabrikant Einar Willumsens Mindelegat
- Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)
- 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)kappa B through G alpha i. 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-NF kappa B 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.
- 15-Jan-2015
- Oncogene, v. 34, n. 3, p. 288-298, 2015.
- 288-298
- Nature Publishing Group
- Epithelial carcinogenesis
- Inflammation
- Keratinocyte stem cells
- Pericellular proteolysis
- http://www.nature.com/onc/journal/v34/n3/full/onc2013563a.html
- Acesso restrito
- outro
- http://repositorio.unesp.br/handle/11449/128404
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