Identification of Immune-Related Gene Signature and Prediction of CeRNA Network in Active Ulcerative Colitis

Abstract

BackgroundUlcerative colitis (UC) is an inflammatory disease of the intestinal mucosa, and its incidence is steadily increasing worldwide. Intestinal immune dysfunction has been identified as a central event in UC pathogenesis. However, the underlying mechanisms that regulate dysfunctional immune cells and inflammatory phenotype remain to be fully elucidated.MethodsTranscriptome profiling of intestinal mucosa biopsies were downloaded from the GEO database. Robust Rank Aggregation (RRA) analysis was performed to identify statistically changed genes and differentially expressed genes (DEGs). Gene Set Enrichment Analysis (GSEA), Gene Ontology (GO), and Kyoto Encyclopedia of Genes and Genomes (KEGG) were used to explore potential biological mechanisms. CIBERSORT was used to evaluate the proportion of 22 immune cells in biopsies. Weighted co-expression network analysis (WGCNA) was used to determine key module-related clinical traits. Protein-Protein Interaction (PPI) network and Cytoscape were performed to explore protein interaction network and screen hub genes. We used a validation cohort and colitis mouse model to validate hub genes. Several online websites were used to predict competing endogenous RNA (ceRNA) network.ResultsRRA integrated analysis revealed 1838 statistically changed genes from four training cohorts (adj. p-value < 0.05). GSEA showed that statistically changed genes were enriched in the innate immune system. CIBERSORT analysis uncovered an increase in activated dendritic cells (DCs) and M1 macrophages. The red module of WGCNA was considered the most critical module related to active UC. Based on the results of the PPI network and Cytoscape analyses, we identified six critical genes and transcription factor NF-κB. RT-PCR revealed that andrographolide (AGP) significantly inhibited the expression of hub genes. Finally, we identified XIST and three miRNAs (miR-9-5p, miR-129-5p, and miR-340-5p) as therapeutic targets.ConclusionsOur integrated analysis identified four hub genes (CXCL1, IL1B, MMP1, and MMP10) regulated by NF-κB. We further revealed that AGP decreased the expression of hub genes by inhibiting NF-κB activation. Lastly, we predicted the involvement of ceRNA network in the regulation of NF-κB expression. Collectively, our results provide valuable information in understanding the molecular mechanisms of active UC. Furthermore, we predict the use of AGP and small RNA combination for the treatment of UC.

The Importance of CXCL1 in the Physiological State and in Noncancer Diseases of the Oral Cavity and Abdominal Organs

“…CXCL1 may be a biomarker for ulcerative colitis [146]. Analyses of changes in gene expression indicate that CXCL1 is a hub gene in ulcerative colitis [151,152]. Additionally, mucosal biopsies from patients with ulcerative colitis show higher expression of another CXCR2 ligand: CXCL8/IL-8 [144,149], which indicates that CXCL1 does not act alone but rather with other CXCR2 ligands.…”

Identification of gene signatures associated with ulcerative colitis and the association with immune infiltrates in colon cancer

“…However, few biomarkers can accurately predict drug sensitivity/resistance in patients with UC. Failure of the immune tolerance mechanism or damaged normal intestinal barrier leads to excessive infiltration of immune cells in lamina propria of the intestine, which is then exposed to invading luminal antigens ( 9 ). These activated immune cells secrete chemokines and cytokines including interferon-γ, interleukins, and tumor necrosis factor (TNF) to promote inflammation ( 10 ).…”

Integrative Analysis and Experimental Validation of Competing Endogenous RNAs in Obstructive Sleep Apnea

“…We further interrogated the potential molecular mechanisms of the ceRNA networks. Intriguingly, upregulation of all three lncRNAs in the ceRNA networks was closely correlated with cell apoptosis and the inflammatory response [ 55 , 56 , 57 , 58 ], as they had been reported to increase the expression level of NF-κB ( Figure 9 ), indicating NF-κB pathway activation in OSA. GO analysis in this study suggested that OSA was closely correlated with altered immune function.…”

“…Accumulating evidence has demonstrated its intricacy in regulating genes involved in cell growth and division, as well as apoptosis, hypoxia, stress, and the immune system. Interestingly, a large body of literature reports that upregulated expression of the lncRNAs in hub ceRNA networks causes the same event, i.e., upregulation of the NF-κB, through distinct molecular mechanisms [ 55 , 56 , 57 , 58 ]. As is well known, CIH in OSA patients can cause oxidative stress, systemic inflammation, and NF-κB-dependent inflammatory pathway activation [ 33 , 76 ], which is the potential pathogenesis of complications such as diabetes mellitus and cardiovascular disorders [ 77 , 78 ].…”