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

Oncogene volume 34, pages 346–356 (2015)Cite this article

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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.

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Acknowledgements

We thank Dr Mary Jo Danton for critically reviewing this manuscript. Histology was performed by Histoserv, Germantown, MD, USA. We thank Dr Allessia Gallo, Shyh-Ing Jang, Colleen Doci, Patricia Pilla, Zhiyong Wang, Canstantinos Mikelis, Ramiro Iglesias-Bartolome and Morgan O’Hare for technical assistance. The study was supported by the NIDCR Intramural Research Program (THB, JSG, WC), the Augustinus Foundation, Kobmand Kristian Kjær og hustrus Foundation, the Kjær-Foundation, the Dagmar Marshalls Foundation, the Snedkermester Sophus Jacobsen og Hustru Astrid Jacobsens Foundation, the Grosserer Valdemar Foersom og Hustru Thyra Foersoms Foundation and Fabrikant Einar Willumsens Mindelegat (SG and LKV), and the Sao Paulo Research Foundation (FAPESP) (MH, SRR).

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Authors and Affiliations

  1. Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA

    K U Sales, S Friis, J E Konkel, S Godiksen, K K Hansen, R Szabo, W Chen, J S Gutkind & T H Bugge

  2. Clinical Research Core, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD, USA

    K U Sales

  3. Department of Cellular and Molecular Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark

    S Friis, S Godiksen & L K Vogel

  4. Department of Biology, Faculty of Science, University of Copenhagen, Copenhagen, Denmark

    S Godiksen

  5. Department of Urology, Faculty of Medicine, Sao Paulo State University (UNESP), Botucatu, Sao Paulo, Brazil

    M Hatakeyama & S R Rogatto

  6. AC Camargo Cancer Center, Sao Paulo, Brazil

    M Hatakeyama & S R Rogatto

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  1. K U Sales
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Correspondence to T H Bugge.

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Sales, K., Friis, S., Konkel, J. et al. Non-hematopoietic PAR-2 is essential for matriptase-driven pre-malignant progression and potentiation of ras-mediated squamous cell carcinogenesis. Oncogene 34, 346–356 (2015). https://doi.org/10.1038/onc.2013.563

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