Abstract
BackgroundThe nuclear factor-kappa B (NF-κB) signalling pathway is a regulator of immune response and inflammation that has been implicated in the carcinogenic process. We examined differentially expressed genes in this pathway and miRNAs to determine associations with colorectal cancer (CRC).MethodsWe used data from 217 CRC cases to evaluate differences in NF-κB signalling pathway gene expression between paired carcinoma and normal mucosa and identify miRNAs that are associated with these genes. Gene expression data from RNA-Seq and miRNA expression data from Agilent Human miRNA Microarray V19.0 were analysed. We evaluated genes most strongly associated and differentially expressed (fold change (FC) of > 1.5 or < 0.67) that were statistically significant after adjustment for multiple comparisons.ResultsOf the 92 genes evaluated, 22 were significantly downregulated and nine genes were significantly upregulated in all tumours. Two additional genes (CD14 and CSNK2A1) were dysregulated in MSS tumours and two genes (CARD11 and VCAM1) were downregulated and six genes were upregulated (LYN, TICAM2, ICAM1, IL1B, CCL4 and PTGS2) in MSI tumours. Sixteen of the 21 dysregulated genes were associated with 40 miRNAs. There were 76 miRNA:mRNA associations of which 38 had seed-region matches. Genes were associated with multiple miRNAs, with TNFSRF11A (RANK) being associated with 15 miRNAs. Likewise several miRNAs were associated with multiple genes (miR-150-5p with eight genes, miR-195-5p with four genes, miR-203a with five genes, miR-20b-5p with four genes, miR-650 with six genes and miR-92a-3p with five genes).ConclusionsFocusing on the genes and their associated miRNAs within the entire signalling pathway provides a comprehensive understanding of this complex pathway as it relates to CRC and offers insight into potential therapeutic agents.
Highlights
The nuclear factor-kappa B (NF-κB) signalling pathway is a key regulator of inflammation and has been associated with carcinogenesis (Merga et al 2016)
Evaluation of microsatellite unstable (MSI)-specific tumours showed that two additional genes were downregulated, CARD11 and VCAM1 (FC 0.37 and 0.59, respectively) and six genes were upregulated (LYN fold change (FC) 1.59, TICAM2 FC 1.64, ICAM1 FC 1.91, IL1B FC 2.06, CCL4 FC 2.72, and PTGS2 FC 3.23) that were statistically significant (Supplemental Table 3 for MSI-specific results)
The NF-κB signalling pathway is important in the carcinogenic process given its role in the regulation of genes both inside and outside of the immune system
Summary
The nuclear factor-kappa B (NF-κB) signalling pathway is a key regulator of inflammation and has been associated with carcinogenesis (Merga et al 2016). The classical or canonical NF-κB signalling pathway is activated by cytokines, such as IL-1 and TNF, T-cell receptors (TCR), or B-cell receptors (BCR) which stimulate the IKK complex, phosphorylating p105 which releases the NF-κB dimers. The alternative pathway (non-canonical pathway) originates through B-cell activation factor (BAFF-R), lymphotoxin β-receptor (LTβR), CF40 receptor activator for nuclear factor-kappa B (RANK), and TNFR2, which in turn activate adaptor protein NF-κB-inducing kinase (NIK) which activates IKKα. We examined differentially expressed genes in this pathway and miRNAs to determine associations with colorectal cancer (CRC). Methods We used data from 217 CRC cases to evaluate differences in NF-κB signalling pathway gene expression between paired carcinoma and normal mucosa and identify miRNAs that are associated with these genes. Conclusions Focusing on the genes and their associated miRNAs within the entire signalling pathway provides a comprehensive understanding of this complex pathway as it relates to CRC and offers insight into potential therapeutic agents
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