title: Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion.
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.
authors.affiliation: Cancer Cell Circuitry Laboratory, Research Programs Unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
authors.forename: T A
authors.initials: TA
authors.lastname: Tervonen
authors.affiliation: Cancer Cell Circuitry Laboratory, Research Programs Unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
authors.forename: D
authors.initials: D
authors.lastname: Belitškin
authors.affiliation: Cancer Cell Circuitry Laboratory, Research Programs Unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
authors.forename: S M
authors.initials: SM
authors.lastname: Pant
authors.affiliation: Cancer Cell Circuitry Laboratory, Research Programs Unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
authors.forename: J I
authors.initials: JI
authors.lastname: Englund
authors.affiliation: Cancer Cell Circuitry Laboratory, Research Programs Unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
authors.forename: E
authors.initials: E
authors.lastname: Marques
authors.affiliation: Cancer Cell Circuitry Laboratory, Research Programs Unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Ala-Hongisto
authors.affiliation: Cancer Cell Circuitry Laboratory, Research Programs Unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
authors.forename: L
authors.initials: L
authors.lastname: Nevalaita
authors.affiliation: Department of Oncology, University of Helsinki & Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Sihto
authors.affiliation: Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: P
authors.initials: P
authors.lastname: Heikkilä
authors.affiliation: Breast Surgery Unit, Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: M
authors.initials: M
authors.lastname: Leidenius
authors.affiliation: Helsinki Innovation Services Ltd, Tukholmankatu 8A, 00290, University of Helsinki, Helsinki, Finland.
authors.forename: K
authors.initials: K
authors.lastname: Hewitson
authors.affiliation: Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore, India.
authors.forename: M
authors.initials: M
authors.lastname: Ramachandra
authors.affiliation: Orion Corporation, Orion Pharma, Turku, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Moilanen
authors.affiliation: Department of Oncology, University of Helsinki & Helsinki University Central Hospital, Helsinki, Finland.
authors.forename: H
authors.initials: H
authors.lastname: Joensuu
authors.affiliation: Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
authors.forename: P E
authors.initials: PE
authors.lastname: Kovanen
authors.affiliation: School of Pharmacy, University of Eastern Finland, Kuopio, Finland and Finnish Institute of Molecular Medicine, Helsinki, Finland.
authors.forename: A
authors.initials: A
authors.lastname: Poso
authors.affiliation: Cancer Cell Circuitry Laboratory, Research Programs Unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
authors.forename: J
authors.initials: J
authors.lastname: Klefström
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D004318:Doxycycline / Q000008:administration & dosage; D004847:Epithelial Cells / Q000378:metabolism / Q000473:pathology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D017228:Hepatocyte Growth Factor / Q000235:genetics*; D006801:Humans; D008321:Mammary Glands, Animal; D051379:Mice; D053491:Proteinase Inhibitory Proteins, Secretory / Q000096:biosynthesis / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics*; D012697:Serine Endopeptidases / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C066855:HGF protein, human; D053491:Proteinase Inhibitory Proteins, Secretory; C109149:SPINT1 protein, human; D017228:Hepatocyte Growth Factor; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D012697:Serine Endopeptidases; C055645:hepsin; D004318:Doxycycline