The serine protease prostasin is a negative regulator of lipopolysaccharide-induced inflammation and has a role in the regulation of cellular immunity.  Prostasin expression in cancer cells inhibits migration and metastasis, and reduces epithelial-mesenchymal transition.  Programmed death-ligand 1 (PD-L1) is a negative regulator of the immune response and its expression in cancer cells interferes with immune surveillance.  The aim of this study was to investigate if prostasin regulates PD-L1 expression.  We established sublines over-expressing various forms of prostasin as well as a subline deficient for the prostasin gene from the Calu-3 human lung cancer cells.  We report here that PD-L1 expression induced by interferon-gamma (IFNg) is further enhanced in cells over-expressing the wild-type membrane-anchored prostasin.  The PD-L1 protein was localized on the cell surface and released into the culture medium in extracellular vesicles (EVs) with the protease-active prostasin.  The epidermal growth factor-epidermal growth factor receptor (EGF-EGFR), protein kinase C (PKC), and mitogen-activated protein kinase (MAPK) participated in the prostasin-mediated up-regulation of PD-L1 expression.  A Gene Set Enrichment Analysis (GSEA) of patient lung tumors in The Cancer Genome Atlas (TCGA) database revealed that prostasin and PD-L1 regulate common signaling pathways during tumorigenesis and tumor progression.

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