title: T-cell-expressed proprotein convertase FURIN inhibits DMBA/TPA-induced skin cancer development.
abstract: Proprotein convertases (PCSK) have a critical role in the body homeostasis as enzymes responsible for processing precursor proteins into their mature forms. FURIN, the first characterized member of the mammalian PCSK family, is overexpressed in multiple malignancies and the inhibition of its activity has been considered potential cancer treatment. FURIN has also an important function in the adaptive immunity, since its deficiency in T cells causes an impaired peripheral immune tolerance and accelerates immune responses. We addressed whether deleting FURIN from the immune cells would strengthen anticancer responses by subjecting mouse strains lacking FURIN from either T cells or macrophages and granulocytes to the DMBA/TPA two-stage skin carcinogenesis protocol. Unexpectedly, deficiency of FURIN in T cells resulted in enhanced and accelerated development of tumors, whereas FURIN deletion in macrophages and granulocytes had no effect. The epidermises of T-cell-specific FURIN deficient mice were significantly thicker with more proliferating Ki67+ cells. In contrast, there were no differences in the numbers of the T cells. The flow cytometric analyses of T-cell populations in skin draining lymph nodes showed that FURIN T-cell KO mice have an inherent upregulation of early activation marker CD69 as well as more CD4+CD25+Foxp3+positive T regulatory cells. In the early phase of tumor promotion, T cells from the T-cell-specific FURIN knockout animals produced more interferon gamma, whereas at later stage the production of Th2- and Th17-type cytokines was more prominent than in wild-type controls. In conclusion, while PCSK inhibitors are promising therapeutics in cancer treatment, our results show that inhibiting FURIN specifically in T cells may promote squamous skin cancer development.
authors.affiliation: School of Medicine, Department of Anatomy and Cell Biology, University of Tampere , Tampere, Finland.
authors.forename: Maria
authors.initials: M
authors.lastname: Vähätupa
authors.affiliation: Immunoregulation, BioMediTech, University of Tampere , Tampere, Finland.
authors.forename: Saara
authors.initials: S
authors.lastname: Aittomäki
authors.affiliation: Immunoregulation, BioMediTech, University of Tampere , Tampere, Finland.
authors.forename: Zuzet
authors.initials: Z
authors.lastname: Martinez Cordova
authors.affiliation: School of Medicine, Department of Anatomy and Cell Biology, University of Tampere , Tampere, Finland.
authors.forename: Ulrike
authors.initials: U
authors.lastname: May
authors.affiliation: School of Medicine, Department of Anatomy and Cell Biology, University of Tampere , Tampere, Finland.
authors.forename: Stuart
authors.initials: S
authors.lastname: Prince
authors.affiliation: Department of Ophthalmology, Tampere University Hospital , Tampere, Finland.
authors.forename: Hannele
authors.initials: H
authors.lastname: Uusitalo-Järvinen
authors.affiliation: School of Medicine, Department of Anatomy and Cell Biology, University of Tampere, Tampere, Finland; Department of Orthopedics & Traumatology, Tampere University Hospital, Tampere, Finland.
authors.forename: Tero A
authors.identifier: 0000-0002-4027-1759
authors.initials: TA
authors.lastname: Järvinen
authors.affiliation: Immunoregulation, BioMediTech, University of Tampere, Tampere, Finland; Department of Dermatology, Tampere University Hospital, Tampere, Finland.
authors.forename: Marko
authors.initials: M
authors.lastname: Pesu
keywords: FURIN; T cells; proprotein convertase; squamous skin cancer; transforming growth factor-β1