Identification and Validation of ATF3 Serving as a Potential Biomarker and Correlating With Pharmacotherapy Response and Immune Infiltration Characteristics in Rheumatoid Arthritis

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.

[Retracted] Identification of Diagnostic Biomarkers, Immune Infiltration Characteristics, and Potential Compounds in Rheumatoid Arthritis

“…The synovial tissue is of interest for gene analysis in RA. In several previous studies on RA, bioinformatic analyses have been performed with the following research objectives: identifying key genes for diagnosis [ 26 – 33 ], immune infiltration [ 28 , 31 – 33 ], and therapeutic targets [ 26 , 32 ]; however, the sample size of these studies was not very large, and the research content that integrates these three research objectives is lacking. Therefore, various bioinformatic tools were used in this study to analyse differentially expressed gene (DEG) data between patients with RA and healthy individuals from the comprehensive gene expression database [ 34 – 38 ].…”

Global trends in research of fibroblasts associated with rheumatoid diseases in the 21st century: A bibliometric analysis

“…Since then, researchers have been able to type the fibroblasts in more detail and focus on a range of signaling pathways that make certain subsets of fibroblasts migratory and invasive. Since 2020, as many molecular mechanisms have become clear and in vitro validation experiments have been carried out, researchers have been committed to verifying and looking for the most reliable therapeutic targets (76,77). With the understanding of the fibroblast pathologic process, how to regulate fibroblast autophagy has become an emerging hot topic.…”

The multifaceted roles of activating transcription factor 3 (ATF3) in inflammatory responses – Potential target to regulate neuroinflammation in acute brain injury

“…66 Therefore, ATF3 can be initially activated by metabolic stressors, then works as a modulator and inhibitor in response to a variety of inflammatory stimuli. 7,12,50,67 Apart from the anti-inflammatory properties mentioned above, persistent ATF3 expression induced by excessive reactive oxygen species (ROS) or ER stress may have detrimental effects, overwhelming its initial compensatory property. For instance, triglyceride-rich lipoprotein (TL) lipolysis products promote nuclear ATF3 accumulation in carotid artery ECs of mice and increase vascular apoptosis, 68 whereas ATF3 promotes lipolysis products-induced transcription of E-selectin and IL-8 in human aortic Ecs.…”

“…[2][3][4] ATF3 is emerging as a master regulator of inflammation in multiple pathophysiological processes such as cardiovascular disease, dementia, and ischemia/reperfusion-induced damage. 1,[5][6][7][8][9][10][11][12][13][14][15] Neuroinflammation is one of the key pathological features of a wide range of acute brain injuries (ABIs), [16][17][18][19] which mainly include stroke and traumatic brain injury (TBI). 20,21 Neuroinflammation plays a pivotal role in ischemic brain injury during the acute phase of ABI, with excessive immune cell activation and the release of inflammatory mediators.…”