Deregulated hepsin protease activity confers oncogenicity by concomitantly augmenting HGF/MET signalling and disrupting epithelial cohesion
Autor: | Heikki Joensuu, Murali Ramachandra, Denis Belitskin, Liina Nevalaita, Päivi Heikkilä, Johanna Englund, Hanna Ala-Hongisto, K Hewitson, Panu E. Kovanen, Shishir M. Pant, Anu Moilanen, Marjut Leidenius, Antti Poso, Harri Sihto, Juha Klefström, Elsa Marques, Topi A. Tervonen |
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Rok vydání: | 2015 |
Předmět: |
0301 basic medicine
Cancer Research Proteases Hepsin medicine.medical_treatment Cell Proteinase Inhibitory Proteins Secretory Breast Neoplasms Biology Serine 03 medical and health sciences Mice Mammary Glands Animal Genetics medicine Animals Humans Molecular Biology Serine protease Protease Hepatocyte Growth Factor Hemidesmosome Serine Endopeptidases Epithelial Cells Proto-Oncogene Proteins c-met Molecular biology Xenograft Model Antitumor Assays Cell biology Gene Expression Regulation Neoplastic 030104 developmental biology medicine.anatomical_structure Doxycycline biology.protein Hepatocyte growth factor Female medicine.drug Signal Transduction |
Zdroj: | Oncogene. 35(14) |
ISSN: | 1476-5594 |
Popis: | 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. |
Databáze: | OpenAIRE |
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