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Matriptase promotes inflammatory cell accumulation and progression of established epidermal tumors

Oncogene volume 34, pages 4664–4672 (2015)Cite this article

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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.

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Acknowledgements

We thank Dr Mary Jo Danton and Dr J Silvio Gutkind for critically reviewing this manuscript. We also thank Andrew Cho and Dr Ashok Kulkarni, NIDCR Gene Targeting Facility, for generation of transgenic mice. Histology was performed by Histoserv, Inc., Germantown, MD, USA. The study was supported by the NIDCR Intramural Research Program (THB), Sao Paulo Research Foundation 2014/14311-0 (KUS), The Harboe Foundation, The Foundation of 17.12.1981 and the Lundbeck Foundation (SF).

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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, L Abusleme, N M Moutsopoulos & 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 Cell and Molecular Biology, Ribeirao Preto School of Medicine, University of Sao Paulo, Ribeirao Preto, Brazil

    K U Sales

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

    S Friis

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Correspondence to T H Bugge.

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Sales, K., Friis, S., Abusleme, L. et al. Matriptase promotes inflammatory cell accumulation and progression of established epidermal tumors. Oncogene 34, 4664–4672 (2015). https://doi.org/10.1038/onc.2014.391

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