title: Matriptase promotes inflammatory cell accumulation and progression of established epidermal tumors.
abstract: Deregulation of matriptase is a consistent feature of human epithelial cancers and correlates with poor disease outcome. We have previously shown that matriptase promotes multi-stage squamous cell carcinogenesis in transgenic mice through dual activation of pro-hepatocyte growth factor-cMet-Akt-mTor proliferation/survival signaling and PAR-2-Gαi-NFκB inflammatory signaling. Matriptase was congenitally and constitutively deregulated in our prior studies, and therefore it was unclear if aberrant matriptase signaling supports only initiation of tumor formation or if it is also critical for the progression of established tumors. To determine this, we here have generated triple-transgenic mice with constitutive deregulation of matriptase and simultaneous inducible expression of the cognate matriptase inhibitor, hepatocyte growth factor inhibitor (HAI)-2. As expected, constitutive expression of HAI-2 suppressed the formation of matriptase-dependent tumors in 7,12-Dimethylbenz(a)anthracene-treated mouse skin. Interestingly, however, the induction of HAI-2 expression in already established tumors markedly impaired malignant progression and caused regression of individual tumors. Tumor regression correlated with reduced accumulation of tumor-associated inflammatory cells, likely caused by diminished expression of pro-tumorigenic inflammatory cytokines. The data suggest that matriptase-dependent signaling may be a therapeutic target for both squamous cell carcinoma chemoprevention and for the treatment of established tumors.
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.|Clinical Research Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.|Department of Cell and Molecular Biology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto, Brazil.
authors.forename: K U
authors.initials: KU
authors.lastname: Sales
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.|Department of Cellular and Molecular Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark.
authors.forename: S
authors.initials: S
authors.lastname: Friis
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: L
authors.initials: L
authors.lastname: Abusleme
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: N M
authors.initials: NM
authors.lastname: Moutsopoulos
authors.affiliation: Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA.
authors.forename: T H
authors.initials: TH
authors.lastname: Bugge
mesh_terms: D000818:Animals; D063646:Carcinogenesis / Q000276:immunology / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000276:immunology / Q000473:pathology; D016207:Cytokines / Q000378:metabolism; D018450:Disease Progression; D005260:Female; D018836:Inflammation Mediators / Q000378:metabolism; D008264:Macrophages / Q000276:immunology; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008822:Mice, Transgenic; D012697:Serine Endopeptidases / Q000502:physiology*; D012878:Skin Neoplasms / Q000201:enzymology* / Q000276:immunology / Q000473:pathology
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D008565:Membrane Proteins; C533525:Spint2 protein, mouse; D012697:Serine Endopeptidases; C485595:matriptase