RESUMO
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.
Assuntos
Transformação Celular Neoplásica/metabolismo , Células Epiteliais/metabolismo , Receptor PAR-2/metabolismo , Serina Endopeptidases/metabolismo , Proteínas ras/metabolismo , Animais , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular , Transformação Celular Neoplásica/genética , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Progressão da Doença , Células Epiteliais/patologia , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/genética , Subunidades alfa Gi-Go de Proteínas de Ligação ao GTP/metabolismo , Células HEK293 , Humanos , Imuno-Histoquímica , Queratinócitos/metabolismo , Camundongos Endogâmicos C57BL , Camundongos Knockout , NF-kappa B/genética , NF-kappa B/metabolismo , Lesões Pré-Cancerosas/genética , Lesões Pré-Cancerosas/metabolismo , Lesões Pré-Cancerosas/patologia , Receptor PAR-2/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Serina Endopeptidases/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/metabolismo , Proteínas ras/genéticaRESUMO
Two new saliva stimulants: V6 and a mucin containing chewing gum were tested in this placebo-controlled double-blind crossover study. Forty-three patients (mean age 63 yr) complaining of dry mouth participated. The products were administered in a randomized order, and used for 2 wk each. The effect was evaluated by interviews and by determining changes in stimulated and unstimulated saliva flow rates. A positive effect was reported by 64%, 44%, and 26% of the patients using the mucin chewing gum, V6, and the placebo, respectively. More than 2/3 of the patients found the mucin chewing gum efficient at various times and situations. Sixty-one percent of the patients preferred the mucin chewing gum, 21% V6, and 5% the placebo product. Fifty percent of the patients had an increase in unstimulated salivary secretion rate from all products after 14 days regular use indicating a long-term effect.