Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion

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Abstract

Hepsin belongs to a family of cell-surface serine proteases, which have sparked interest as therapeutic targets because of the accessibility of extracellular protease domain for inhibitors. Hepsin is frequently amplified and/or overexpressed in epithelial cancers, but it is not clear how enhanced hepsin expression confers a potential for oncogenicity. We show that hepsin is consistently overexpressed in more than 40% of examined breast cancers, including all major biological subtypes. The effects of doxycycline-induced hepsin overexpression were examined in mammary epithelial organoids, and we found that induced hepsin acutely downmodulates its cognate inhibitor, hepatocyte growth factor (HGF) activator inhibitor type 1 (HAI-1). Hepsin-induced depletion of cellular HAI-1 led to a sharp increase in pericellular serine protease activity. The derepressed hepsin proteolytically activated downstream serine proteases, augmented HGF/MET signalling and caused deterioration of desmosomes and hemidesmosomes; structures important for cell cohesion and cell-basement membrane interaction. Moreover, chronic induction of hepsin considerably shortened the latency of Myc-dependent tumourigenesis in the mouse mammary gland. The serine protease and uPA system inhibitor WX-UK1, identified as a micromolar range hepsin inhibitor, prevented hepsin from augmenting HGF/MET signalling and disrupting desmosomes and hemidesmosomes. The findings suggest that the oncogenic activity of hepsin arises not only from elevated expression level but also from depletion of HAI-1, events which together trigger gain-of-function activity impacting HGF/MET signalling and epithelial cohesion. Thus, hepsin overexpression is a major oncogenic conferrer to a serine protease activity involved in breast cancer dissemination.

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Acknowledgements

We thank all the members of Klefström laboratory for discussions and critical comments on the manuscript. T Raatikainen and T Välimäki are thanked for technical assistance. Biomedicum Imaging Unit and Biomedicum Functional Genomics Unit are acknowledged for core services and technical support. This study was funded by the Academy of Finland, Sigrid Jusélius Foundation, the Finnish Cancer Society, the Research Funds of the Helsinki University Central Hospital, Jane and Aatos Erkko Foundation, and Helsinki Graduate Program in Biotechnology and Molecular Biology and Innovative Medicines Initiative Joint Undertaking under grant agreement n°115188.

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Correspondence to J Klefström.

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Tervonen, T., Belitškin, D., Pant, S. et al. Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion. Oncogene 35, 1832–1846 (2016). https://doi.org/10.1038/onc.2015.248

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