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

  • Oncogene. 2016 Apr 7;35(14):1832-46. doi: 10.1038/onc.2015.248.
T A Tervonen  1 ,  D Belitškin  1 ,  S M Pant  1 ,  J I Englund  1 ,  E Marques  1 ,  H Ala-Hongisto  1 ,  L Nevalaita  1 ,  H Sihto  2 ,  P Heikkilä  3 ,  M Leidenius  4 ,  K Hewitson  5 ,  M Ramachandra  6 ,  A Moilanen  7 ,  H Joensuu  2 ,  P E Kovanen  3 ,  A Poso  8 ,  J Klefström  1
Affiliations
  • 1. Cancer Cell Circuitry Laboratory, Research Programs Unit, Translational Cancer Biology and Institute of Biomedicine, University of Helsinki, Helsinki, Finland.
  • 2. Department of Oncology, University of Helsinki & Helsinki University Central Hospital, Helsinki, Finland.
  • 3. Department of Pathology, HUSLAB and Haartman Institute, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
  • 4. Breast Surgery Unit, Helsinki University Central Hospital, Helsinki, Finland.
  • 5. Helsinki Innovation Services Ltd, Tukholmankatu 8A, 00290, University of Helsinki, Helsinki, Finland.
  • 6. Aurigene Discovery Technologies Limited, 39-40 KIADB Industrial Area, Electronic City Phase II, Bangalore, India.
  • 7. Orion Corporation, Orion Pharma, Turku, Finland.
  • 8. School of Pharmacy, University of Eastern Finland, Kuopio, Finland and Finnish Institute of Molecular Medicine, Helsinki, Finland.
PMID: 26165838 DOI: 10.1038/onc.2015.248
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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