In silico pathway and network-based analysis to identify potential gene therapy targets for inflammatory bowel disease

Background and Aim: Inflammatory bowel disease (IBD) is a chronic disorder of the gastrointestinal tract which subdivides into ulcerative colitis (UC) and Crohn’s disease (CD). IBD patients are ۲–۶ times more prone to colorectal cancer (CRC) than the general population. About ۱۰– ۱۵% of the annual deaths in IBD patients are caused by IBD-related CRC. Nowadays, available IBD drugs aim to induce deep remission of symptoms. Here we’re going to propose gene therapy targets for IBD, based on common pathways with CRC which may represent a robust therapeutic and chemo-preventive approach.Methods: Gene expression datasets for IBD and CRC were extracted from “GEO” database. Data normalization, batch effect removal, and calculation of differential expression of genes were carried out using R software packages. The cut-off criteria used for selecting significant up-regulated genes in each disease were adjusted p-value<۰.۰۵ and log۲-fold change>+۱. A gene set consisted of common up-regulated genes among all conditions underwent enrichment analysis using “Enrichr” webserver. Significant up-regulated pathways were selected applying adjusted p-value<۰.۰۵ filter. Subsequently, KEGG mapper online tool was employed for pathway analysis in order to find critical genes. On the other hand, a protein-protein interaction network of common up-regulated genes in different diseases was conducted using “STRING” (version ۱۱.۰) and results were analyzed and visualized using “Cytoscape” (version ۳.۷.۲) to find the hub genes. Gene set enrichment analysis was carried out for a new gene set including critical genes in pathways and hub genes in network as potential therapeutic targets. Ultimately, significant co-expressed transcription factors were mined from ARCHS۴ database.Results: We identified ۳۳ common up-regulated genes in primary CRC, CD, UC and Colon Polyps. Chemokine signaling pathways mainly IL۱۷ and TNF were common among all conditions. MMP۱, MMP۳, CXCL۱, CXCL۲, CXCL۳, CXCL۸, CCL۲۰, LCN۲ as critical genes in pathways and CXCL۸, CXCL۱, GDF۱۵, CXCL۲ as hub genes were expressed along with transcription factors, ETV۳L and MTF۱.Conclusion: It seems that IBD is linked with CRC through up-regulation of inflammatory signaling pathways. Therefore, down-regulation of ETV۳L and MTF۱ through silencing or knocking out is likely to be a potential modality for IBD treatment against future malignancies.

کلیدواژه ها:

Inflammatory bowel disease ، gene therapy ، in silico ، pathway analysis ، network analysis