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Oncogene. 2016 Apr 7;35(14):1832-46. doi: 10.1038/onc.2015.248. Epub 2015 Jul 13.

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

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Cancer Cell Circuitry Laboratory, Research Programs Unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
Department of Oncology, University of Helsinki & Helsinki University Central Hospital, Helsinki, Finland.
Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
Breast Surgery Unit, Helsinki University Central Hospital, Helsinki, Finland.
Helsinki Innovation Services Ltd, Tukholmankatu 8A, 00290, University of Helsinki, Helsinki, Finland.
Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore, India.
Orion Corporation, Orion Pharma, Turku, Finland.
School of Pharmacy, University of Eastern Finland, Kuopio, Finland and Finnish Institute of Molecular Medicine, Helsinki, Finland.


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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