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.
Subject(s)
Cell Transformation, Neoplastic/metabolism , Epithelial Cells/metabolism , Receptor, PAR-2/metabolism , Serine Endopeptidases/metabolism , ras Proteins/metabolism , 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/geneticsABSTRACT
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.
