چکیده:
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 GSE87473 and GSE44076 expression profiles were downloaded from the Gene Expression Omnibus (GEO). GSE87473 contains 21 healthy samples, 27 extensive ulcerative colitis samples and 60 limited ulcerative colitis samples. GSE44076 contains 98 colon cancer samples and 98 healthy samples.
The inclusion criteria for the differentially expressed genes (DEGs) included an adjusted p-value 2. 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 <0. 05 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, 187,139 and 221 genes with adjusted p-value 2 were detected respectively. Using Cytoscape software, the genes with degree> 20 including MYC, CD44, TIMP1, MMP3, SPP1, CXCL8 and MMP1 were explored as hub genes in colon cancer. According to inclusion criteria and venn diagram, MMP1, MMP3 and TIMP1 were common genes in three groups and SPP1 was common gene in extensive ulcerative colitis and colon cancer. The genes MYC, CD44 were distinctive genes in colon cancer. In extensive ulcerative colitis, the genes with degree> 30 including IL1B, MMP9, CXCL8, CCL2, CXCL10, CXCL1, PTGS2 and LCN2 were identified as hub genes. Moreover, the genes including IL1B, CXCL8, MMP9, CXCL1 and CXCL10 were detected as hub genes with degree> 30 in limited ulcerative colitis. IL1B, MMP9, CXCL8, CXCL10, CXCL1 and PTGS2 were common genes in extensive ulcerative colitis and limited ulcerative colitis and LCN2 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 CD44 and SPP1were enriched in ECM-receptor interaction. Moreover, hub genes MMP1 and MMP3 were enriched in IL-17 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-17 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, TIMP1 (Metalloproteinase inhibitor 1) , IL1B (Interleukin-1 beta) and PTGS2 (Prostaglandin G/H synthase 2) were with poor overall survival. The present in silico study showed that TIMP1, IL1B and PTGS2 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.