Role of Matriptase and Proteinase-Activated Receptor-2 in Nonmelanoma Skin Cancer

Bocheva, Georgeta; Rattenholl, Anke; Kempkes, Cordula; Goerge, Tobias; Lin, Chen‐Yong; D’Andrea, Michael R.; Ständer, Sonja; Steinhoff, Martin

doi:10.1038/jid.2008.449

Cited by 42 publications

(41 citation statements)

References 27 publications

(36 reference statements)

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“…The 70-kDa matriptase band is therefore most likely to be the latent matriptase. The latent 70-kDa matriptase was also detected in normal human skin by immunoblot under reducing and boiled conditions in another previous study (6). Interestingly, although a 130-kDa protein band was also detected in this study, this 130-kDa protein band should not be the matriptase-HAI-1 complex that should have been dissociated under boiling treatment.…”

Section: Discussionmentioning

confidence: 73%

Increased matriptase zymogen activation in inflammatory skin disorders

Chen¹,

Wu²,

Tsao³

et al. 2011

American Journal of Physiology-Cell Physiology

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Matriptase, a type 2 transmembrane serine protease, and its inhibitor hepatocyte growth factor activator inhibitor (HAI)-1 are required for normal epidermal barrier function, and matriptase activity is tightly regulated during this process. We therefore hypothesized that this protease system might be deregulated in skin disease. To test this, we examined the level and activation state of matriptase in examples of 23 human skin disorders. We first examined matriptase and HAI-1 protein distribution in normal epidermis. Matriptase was detected at high levels at cell-cell junctions in the basal layer and spinous layers but was present at minimal levels in the granular layer. HAI-1 was distributed in a similar pattern, except that high-level expression was retained in the granular layer. This pattern of expression was retained in most skin disorders. We next examined the distribution of activated matriptase. Although activated matriptase is not detected in normal epidermis, a dramatic increase is seen in keratinocytes at the site of inflammation in 16 different skin diseases. To gain further evidence that activation is associated with inflammatory stimuli, we challenged HaCaT cells with acidic pH or H2O2 and observed matriptase activation. These findings suggest that inflammation-associated reactive oxygen species and tissue acidity may enhance matriptase activation in some skin diseases.

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Section: Discussionmentioning

confidence: 73%

Increased matriptase zymogen activation in inflammatory skin disorders

Chen¹,

Wu²,

Tsao³

et al. 2011

American Journal of Physiology-Cell Physiology

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“…In this regard, a wealth of evidence has coalesced within the past decade to implicate the aberrant expression and activity of the epithelial membrane-anchored serine protease, matriptase, to the genesis and progression of human epithelial cancers. Matriptase is near ubiquitously expressed in the epithelial compartment of both pre-malignant and malignant human tissues, where its activity is derailed in a variety of manners that include overexpression, misexpression, and loss of posttranscriptional regulation by cognate protease inhibitors (2–15), reviewed in (16, 17). For example, during multi-stage squamous cell carcinogenesis, matriptase expression undergoes a remarkable translocation from post-mitotic suprabasal cells to proliferative cells of the basal compartment, including epithelial stem cells with tumorigenic potential (13, 18).…”

Section: Introductionmentioning

confidence: 99%

“…In this study, we determined the specific contribution of PAR-2 to the oncogenic activity of matriptase, because matriptase-induced squamous cell carcinogenesis is preceded by a signature chronic inflammation, and because the protease and the G-protein coupled receptor are co-expressed in normal squamous epithelium and in squamous cell carcinoma (15, 19, 42). We took advantage of the fact that PAR-2 deficiency in mice causes partial embryonic lethality, but that born offspring is healthy and display normal long-term survival, thus enabling the use of a definitive genetic epistasis analysis to address this issue (21, 43).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2014

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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 NFκB 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.

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“…These membrane-anchored serine proteases are synthesized as type I transmembrane, type II transmembrane, or glycosylphosphatidylinositol (GPI)-anchored proteins. The truncated recombinant catalytic domains of several of the type II transmembrane serine proteases have been shown to proteolytically activate PAR-2 in vitro, including matriptase, HAT, and TMPRSS2 (11)(12)(13)(14)(15). Whether this activity occurs while these proteases are anchored on the cell surface has been less well studied, with the exception of matriptase, which has been shown to activate PAR-2 when expressed as a full-length protein in cells (16 -19).…”

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confidence: 99%