Proprotein convertase subtilisin/kexin type 6 promotes in vitro proliferation, migration and inflammatory cytokine secretion of synovial fibroblast-like cells from rheumatoid arthritis via nuclear-κB, signal transducer and activator of transcription 3 and extracellular signal regulated 1/2 pathways

Abstract

Our previous studies demonstrated that expression of proprotein convertase subtilisin/kexin type 6 (PCSK6) is greatly enhanced in rheumatoid arthritis fibroblast‑like synoviocytes (RASFs), and that PCSK6 inhibition decreases cell proliferation, migration and invasion. The present study aimed to investigate the functional role of PCSK6 in the hyperplasia of RASFs. Cultured RASFs from RA patients were stimulated with recombinant human (rh)PCSK6. Subsequent changes in proliferation, invasion, migration and the secretion of inflammatory cytokines were measured in vitro using MTT, wound healing and Transwell assays, and ELISA. Cell cycle and apoptosis were analyzed by flow cytometry. Influence on downstream gene expression levels were analyzed using reverse transcription‑quantitative polymerase chain reaction. Specific signaling pathways responsible for these effects were analyzed using western blotting and confirmed with pathway‑specific inhibitors. It was demonstrated that rhPCSK6 significantly increased RASF cell invasion, migration and proliferation, which was influenced through both reduced cell cycle arrest and reduced apoptosis. Furthermore, rhPCSK6 stimulated RASFs to secrete the inflammatory cytokines interleukin (IL)‑1α, IL‑1β and IL‑6, and exhibit altered expression of genes involved in angiogenesis, hypoxia, proliferation and inflammation. These cellular effects were mediated via the nuclear factor (NF)‑κB, signal transducer and activator of transcription 3 (STAT3) and extracellular signal regulated (ERK)1/2 signaling pathways. The results demonstrated that signaling via NF‑κB and STAT3 mediated cell cycle arrest, and signaling through NF‑κB mediated apoptosis in RASF cells stimulated with PCSK6. PCSK6 can activate NF‑κB, STAT3 and ERK1/2 signaling pathways in vitro to enhance cell proliferation, migration, invasion and inflammation in RASF cells. These findings suggest that PCSK6 may be an important therapeutic target in RA.

Nasal DNA methylation profiling of asthma and rhinitis

“…35 A total of 20 CpG site-gene pairs showed significant association between CpG sites and genes where the CpG sites were located, including PCSK6 (proprotein convertase subtilisin/kexin type 6), FBXL7 (F-box and leucine rich repeat protein 7), and CISH (cytokine inducible SH2 containing protein). The following genes have previously been associated with allergic diseases or inflammation: PCSK6, which can activate the NF-kB signaling pathway and is involved in the inflammatory response 36 ; FBXL7, expression of which is involved in the inhaled corticosteroid response in asthma 37 ; and CISH, which showed increased expression levels in human airway eosinophils after allergen challenge. 38 Genes identified by eQTM were enriched in pathways related to immune functions and inflammatory responses.…”

Implications of Angiogenesis Involvement in Arthritis

“…Evidence suggests that proprotein convertase subtilisin/kexin type 6 (PCSK6) may serve as an important therapeutic target in RA. Stimulation with recombinant human (rh)PCSK6 of cultured RASFs from RA patients significantly increased RASF cell invasion, migration, and proliferation, which was influenced through both reduced cell cycle arrest and reduced apoptosis [ 42 ]. rhPCSK6 also stimulated RASFs to secrete IL-1α, IL-1β, and IL-6, and altered gene expression patterns involved in angiogenesis, hypoxia, proliferation, and inflammation.…”

Gene-level germline contributions to clinical risk of recurrence scores in Black and White breast cancer patients

“…For example, VAV3 activates RAC1 which upregulates ESR1 but such mechanistic evidence is sparse for other putative TWAS-gene to PAM50 gene associations [57, 58]. More generally, two of the TWAS-genes among WW ( FAM64A, PCSK6 ) have been found to activate the oncogenic STAT3 signaling pathway, housing many purported anti-cancer drug targets [59, 60].…”