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.

Pan-Cancer Analysis of FURIN as a Potential Prognostic and Immunological Biomarker

“…In pancreatic cancer, furin contributes to epithelialmesenchymal transition through the Hippo-YAP pathway and may be used as a therapeutic target (Zhang et al, 2017). In squamous skin cancer, the inhibition of furin in T cells increased immune responses, impaired peripheral immune tolerance, and promoted cancer development (Ortutay et al, 2015;Vähätupa et al, 2016). Furin is also responsible for the progression and metastasis in LUAD and ovarian cancer (Ma et al, 2014;Chen et al, 2020).…”

Treatment of keloid scars with intralesional triamcinolone and 5-fluorouracil injections – a randomized controlled trial

“…Hematoxylin/eosin staining and immunohistochemical staining (IHC) was performed from 6-μm thick paraffin sections as previously described. 15,16 Briefly, Formalin fixed, paraffin-embedded tissue sections were deparaffinized, processed with appropriate antigen retrieval solution (10 mM Tris-HCL, 1 mM EDTA, pH 9), incubated with the blocking reagent (10% normal goat serum, 5% non-fat milk and 5% BSA), and endogenous peroxidase activity was suppressed with hydrogen peroxide. Tissue sections were incubated with the primary antibody overnight at 4 °C.…”

A new immune signature for survival prediction and immune checkpoint molecules in lung adenocarcinoma

“…Among them, FURIN correlates with many cancer-related processes such as cell proliferation, migration, invasion, and angiogenesis, which promotes tumor progression [39]. FURIN has also a crucial function in the adaptive immunity [40]. PSMD14 induces cell cycle and senescence and may participate in the role of the proteasome [41,42].…”