Upregulation of Hub Gene RRM2 Promotes Progression of Rheumatoid Arthritis

Abstract

Background: Rheumatoid arthritis (RA) is a chronic inflammatory joint disease with autoimmune features, but its molecular mechanism(s) remain unclear. Methods: We analyzed differentially expressed genes (DEGs) using GSE55235, GSE55457, and GSE1919 datasets downloaded from the Gene Expression Omnibus database. We analyzed co-expressed DEGs in GSE55235 and GSE55457 using Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) and a protein-protein interaction (PPI) network of the co-expressed DEGs constructed using STRING and Cytoscape. The top20 hub genes were screened, and targeted miRNAs were identified using TargetScan v. 7.1. The relative expression of hub genes in clinical specimens and in TNF-α-stimulated synovial cells was analyzed by real-time PCR. Results: We extracted 1123 and 333 DEGs in GSE55235 and GSE55457, respectively based on cutoff criteria of |log₂ (FC)| > 1 and adjusted p < 0.05. We found 174 overlapping genes comprising 137 upregulated and 37 downregulated DEGs in patients with RA. Gene Set Enrichment Analysis (GSEA) revealed activated cytokine-cytokine receptor interaction and chemokine signaling pathway cell adhesion molecules (CAMS) in RA lesions. RT-PCR analysis revealed significantly upregulated expression of the hub genes, cluster of differentiation (CD)2, cell division cycle protein 20 homolog (CDC20), and kinesin family member 11 (KIF11) in patients with RA compared with controls and in the GSE1919 dataset. Moreover, miR-106a-5p, miR-20a-5p, and miR-17-5p might negatively regulate the relative expression of ribonucleotide reductase regulatory subunit M2 (RRM2) during RA progression. Conclusions: We identified and validated hub gene expression in RA pathogenesis, and found that the key miRNAs, miR-106a-5p, miR-20a-5p, and miR-17-5p might negatively regulate RRM2 expression during RA progression. These novel hub genes might help to clarify the RA pathogenesis and lead to novel strategies for RA treatment.