Identification of upregulated prognostic biomarkers and key pathways in colon cancer and ulcerative colitis using computational integrative analysis.

Colitis-associated cancer is a major cause of death in patients with ulcerative colitis. A comprehensive understanding of biomarkers and molecular mechanisms can help researchers and physicians to explore novel approaches for the prevention and management of colitis-associated cancer.The GSE۸۷۴۷۳ and GSE۴۴۰۷۶ expression profiles were downloaded from the Gene Expression Omnibus (GEO). GSE۸۷۴۷۳ contains ۲۱ healthy samples, ۲۷ extensive ulcerative colitis samples and ۶۰ limited ulcerative colitis samples. GSE۴۴۰۷۶ contains ۹۸ colon cancer samples and ۹۸ healthy samples. The inclusion criteria for the differentially expressed genes (DEGs) included an adjusted p-value <۰.۰۵ and a log(۲) fold change >۲. Venn diagram of DEGs was depicted for every three groups (extensive ulcerative colitis, limited ulcerative colitis and colon cancer). Protein-protein interaction (PPI) network of DEGs in every three groups was constructed using STRING online database. The DEGs of each group were imported to Cytoscape software separately and the hub genes were screened. Then, the Enrichr web server was used to perform KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analyses and adjusted p-value<۰.۰۵ was considered statistically significant. Moreover, the overall survival (OS) of hub genes was analyzed using Kaplan-Meier curve in GEPIA (http://gepia.cancer-pku.cn/).In extensive ulcerative colitis, limited ulcerative colitis and colon cancer groups, ۱۸۷,۱۳۹ and ۲۲۱ genes with adjusted p-value<۰.۰۵ and log(۲) fold change>۲ were detected respectively. Using Cytoscape software, the genes with degree> ۲۰ including MYC, CD۴۴, TIMP۱, MMP۳, SPP۱, CXCL۸ and MMP۱ were explored as hub genes in colon cancer. According to inclusion criteria and venn diagram, MMP۱, MMP۳ and TIMP۱ were common genes in three groups and SPP۱ was common gene in extensive ulcerative colitis and colon cancer. The genes MYC, CD۴۴ were distinctive genes in colon cancer. In extensive ulcerative colitis, the genes with degree>۳۰ including IL۱B, MMP۹, CXCL۸, CCL۲, CXCL۱۰, CXCL۱, PTGS۲ and LCN۲ were identified as hub genes. Moreover, the genes including IL۱B, CXCL۸, MMP۹, CXCL۱ and CXCL۱۰ were detected as hub genes with degree>۳۰ in limited ulcerative colitis. IL۱B, MMP۹, CXCL۸, CXCL۱۰, CXCL۱ and PTGS۲ were common genes in extensive ulcerative colitis and limited ulcerative colitis and LCN۲ was common gene in three groups. According to KEGG enrichment analysis, hub gene MYC with the most degree in colon cancer was enriched in Hippo signaling pathway, Wnt signaling pathway, Cell cycle, Transcriptional misregulation in cancer and TGF-beta signaling pathway. Hub genes CD۴۴ and SPP۱were enriched in ECM-receptor interaction. Moreover, hub genes MMP۱ and MMP۳ were enriched in IL-۱۷ signaling pathway, TNF signaling pathway, Transcriptional mis-regulation in cancer and PPAR signaling pathway. The hub genes in extensive and limited ulcerative colitis were enriched in IL-۱۷ signaling pathway, TNF signaling pathway, NOD-like receptor signaling pathway, Toll-like receptor signaling pathway, NF-kappa B signaling pathway, Transcriptional misregulation in cancer, Chemokine signaling pathway and Cytokine-cytokine receptor interaction. According to survival analysis, TIMP۱(Metalloproteinase inhibitor ۱), IL۱B (Interleukin-۱ beta) and PTGS۲ (Prostaglandin G/H synthase ۲) were with poor overall survival. The present in silico study showed that TIMP۱, IL۱B and PTGS۲ genes may serve as the prognostic biomarkers in colon cancer. Identification of distinctive and common genes between ulcerative colitis and colon cancer can be useful in the early stage and advanced detection of disease and reducing risk of tumorigenesis and timely treatment .

کلیدواژه ها:

biomarker ، signaling pathway ، overall survival ، ulcerative colitis ، colon cancer