Identification of genes regulating TRAIL-induced apoptosis in rheumatoid arthritis fibroblasts-like synoviocytes

Abstract

We previously described that sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis varied in rheumatoid arthritis fibroblasts-like synoviocytes (RAFLS) from one patient to another and was correlated with disease severity. Therefore, we screened for genes differentially expressed in RAFLS sensitive and resistant to TRAIL-induced apoptosis. The sensitivity of RAFLS was defined based on the percentage of TRAIL-induced apoptosis: 0-10% for resistant cells and >25% for sensitive RAFLS. We performed transcriptomic comparison between RAFLS-S (n=6) and RAFLS-R (n=6) and then examined the implication of identified candidates in the regulation of apoptosis using small interference RNA (siRNA). Microarray analysis revealed 10 functional genes differentially expressed according to TRAIL sensitivity. These factors are implicated in different functions, such as the respiratory chain (ND3), the transport of lipids (OSBP2, PLTP), the regulation of signaling linked to extracellular factors (SULF2, GALNT1, SIAE) or the regulation of gene expression (TET2 and LARP6). We confirmed differential expression for GALNT1 and LARP6 by quantitative reverse transcriptase-PCR. Using siRNA extinction, we demonstrated the implication of GALNT1, SULF2 and LARP6 in the control of TRAIL-induced responses. These results are of particular interest as GALNT1 and LARP6 have been implicated in the regulation of cell death and may represent interesting targets to induce apoptosis of RAFLS.

Maternal Larp6 controls oocyte development, chorion formation and elevation

“…Although La, the founding member of the Larp family, was first discovered as an auto-antigen in individuals with lupus erythromatosis and Sjögren's syndrome, and genetic variation of LARP1, LARP4A, LARP4B and LARP7 are observed in cancers, the role of LARP6 in human disease is as yet unclear (Maraia et al, 2017). LARP6 polymorphism has been linked to susceptibility to type II diabetes, rheumatoid arthritis and coronary artery disease, and the protein is upregulated in some breast cancers and can promote angiogenesis (Assimes et al, 2016;Audo et al, 2015;Shao et al, 2012;Strawbridge et al, 2011). Moreover, LARP6 expression is altered by anti-hepatocellular carcinoma drug sorafenib and has effects on molecules linked to cell proliferation and migration (Cervello et al, 2012;Weng et al, 2009).…”

Acheron/Larp6 Is a Survival Protein That Protects Skeletal Muscle From Programmed Cell Death During Development

“…It also confers a growth advantage for some tumors, such as triple-negative basal-like breast cancers, where it helps drive angiogenesis and invasiveness (Shao et al, 2012). Acheron also protects rheumatoid arthritis fibroblastic synoviocytes from apoptosis induced by the death ligand TRAIL (Audo et al, 2015). Taken together, these various lines of evidence suggest that Acheron functions as a novel survival protein that can protect cells from cell death.…”

Impact of Altered WNT2B Expression on Bladder Wall Fibroblasts: Implications for Apoptosis Regulation in the Stroma of the Lower Urinary Tract

“…This change in TNFSF10 expression was also found in fibrotic VUAS tissue. Since TRAIL, the protein coded by TNFSF10, is a strong inductor of apoptosis, its underexpression might result in the suppression of apoptosis induction [25] and be a surrogate for a more deregulated proliferation: In rheumatoid arthritis, fibroblast-like synoviocytes leads to an increased resistance against TRAIL-induced apoptosis correlated with disease severity [26]. …”