Abstract
Background: Although disease-modifying antirheumatic drugs (DMARDs) have significantly improved the prognosis of patients with rheumatoid arthritis (RA), approximately 40% of RA patients have limited response. Therefore, it was essential to explore new biomarkers to improve the therapeutic effects on RA. This study aimed to develop a new biomarker and validate it by an in vitro study. Methods: The RNA-seq and the clinicopathologic data of RA patients were downloaded from Gene Expression Omnibus (GEO) databases. Differentially expressed genes were screened in the GPL96 and GPL570 databases. Then, weighted gene co-expression network analysis (WGCNA) was used to explore the most correlated gene modules to normal and RA synovium in the GPL96 and GPL570 databases. After that, the differentially expressed genes were intersected with the correlated gene modules to find the potential biomarkers. The CIBERSORT tool was applied to investigate the relationship between activated transcription factor 3 (ATF3) expression and the immune cell infiltration, and Gene Set Enrichment Analysis (GSEA) was used to investigate the related signaling pathways of differentially expressed genes in the high and low ATF3 groups. Furthermore, the relationships between ATF3 expression and clinical parameters were also explored in the GEO database. Finally, the role of ATF3 was verified by in vitro cell experiments. Results: We intersected the differentially expressed genes and the most correlated gene modules in the GPL570 and GPL96 databases and identified that ATF3 is a significant potential biomarker and correlates with some clinical–pharmacological variables. Immune infiltration analysis showed that activated mast cells had a significant infiltration in the high ATF3 group in the two databases. GSEA showed that metabolism-associated pathways belonged to the high ATF3 groups and that inflammation and immunoregulation pathways were enriched in the low ATF3 group. Finally, we validated that ATF3 could promote the proliferation, migration, and invasion of RA fibroblast-like synoviocyte (FLS) and MH7A. Flow cytometry showed that ATF3 expression could decrease the proportion of apoptotic cells and increase the proportion of S and G2/M phase cells. Conclusion: We successfully identified and validated that ATF3 could serve as a novel biomarker in RA, which correlated with pharmacotherapy response and immune cell infiltration.
Highlights
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovitis and joint destruction, which affects approximately 1% of the population in the world (Smolen et al, 2016; Myasoedova et al, 2020)
A prospective cohort study in BMJ explored the effectiveness of rituximab, abatacept, and tocilizumab in adult RA patients with poor response to TNF inhibitors, and it was found that compared with abatacept, rituximab and tocilizumab could significantly improve average durations of survival in those refractory RA patients (Gottenberg et al, 2019)
We investigated the relationships between ATF3 and some pharmacotherapy response parameters, like infliximab response, tocilizumab response, and methotrexate response
Summary
Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovitis and joint destruction, which affects approximately 1% of the population in the world (Smolen et al, 2016; Myasoedova et al, 2020). FLSs, a key component of invasive pannus, play an important role in the pathogenesis of RA (Alsaleh et al, 2011; Quirke et al, 2011; Nygaard and Firestein, 2020). Disease-modifying antirheumatic drugs (DMARDs) have significantly improved the prognosis of patients with RA, approximately 40% of RA patients have a poor response and suffer from pain and loss of daily living activities, which increase the financial burden of RA patients and expose patients to potential therapeutic side effects (Humby et al, 2021). Disease-modifying antirheumatic drugs (DMARDs) have significantly improved the prognosis of patients with rheumatoid arthritis (RA), approximately 40% of RA patients have limited response. It was essential to explore new biomarkers to improve the therapeutic effects on RA. This study aimed to develop a new biomarker and validate it by an in vitro study
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