UC is a common chronic colorectal inflammation that is caused by the dysregulation of the immune response of the genetically susceptible host to an intraluminal antigen[9,10]with recurrent mucus pus and bloody stools, abdominal pain and diarrhea as the main clinical manifestations. With the emergence of UC research, many potential biomarkers for early diagnosis or treatment of UC have been identified after the development of biology technology. However, the mechanism of UC is still unknown.
UC gene expression data were analyzed by WGCNA in this study. We screened a total of 988 DEGs between UC samples and control samples, and identified 5 modules. The brown module was related to the occurrence of UC, and the turquoise module was related to the development of UC. Furthermore, the DEGs in the brown module were mainly involved in functions such as inflammatory responses and pathways such as chemokine signaling pathways. The DEGs in the turquoise module were mainly involved in functions such as oxidation-reduction processes and pathways such as various metabolic pathways. The hub genes DUOXA2,SAA1, SAA2,TNIP3,CXCL1,SLC6A14 and CD55were identified as potential tissue biomarkers for UC diagnosis.
DUOXA2 is the maturation partner of DUOX2,the results demonstrated that both DUOX2 and DUOXA2 were up-regulated in association with inflammation in UC, as well as in colorectal cancer,UC-associated adenomas and colorectal dysplasia. DUOX2 /DUOXA2 provided the NADPH oxidase family that directly generates H2O2, which is involved in inflammatory reactions and can cause DNA single-strand and double-strand breaks[12,13]. These results suggest that DUOX2/DUOXA2 may be involved in the development and carcinogenesis of UC.SAA is a sensitive acute phase protein and a precursor of amyloid A (AA). Because it has higher sensitivity and specificity than C-reactive protein (CRP),SAA can better reflect inflammation, making SAA a protein of current great interest in medical and health fields. Furthermore, as a pro-inflammatory cytokine, SAA plays an important role in the occurrence and development of autoimmune diseases, such as ankylosing spondylitis (AS),rheumatoid arthritis (RA), and inflammatory bowel disease(IBD)[14–16]. Acute SAA(A-SAA),includingSAA1 and SAA2, are produced by hepatocytes and then enter the blood. The SAA1 gene is expressed in colon carcinomas, and it is a chemoattractant that promotes the migration, adhesion and tissue infiltration of monocytes and polymorphonuclear leukocytes . Microarray assessments showed significant over expression of SAA1 in UC specimens. SAA1 plays a role in local inflammation in the microenvironment of malignant tissue and is expressed in colon carcinomas. Therefore, SAA may be a new early predictive clinical marker and a target for designing novel selective inhibitors for therapeutic intervention of UC and UC-associated CRC.
Nuclear factor (NF)-κB plays an important role in the immune system, and inappropriate NF-κB activity is associated with many inflammatory diseases and autoimmune diseases. TNFAIP3 is a key participant in the negative feedback regulation of NF-κB signal transduction in response to multiple stimuli. Recent genetic studies have demonstrated that several mutations in human TNFAIP3 locus are associated with UC, Crohn’s disease, RA, type 1 diabetes mellitus and systemic lupus erythematosus [20–24]. Lee SH showed that TNIP3 over expression down regulated the activation of signal transducer and activator of transcription 3(STAT3) and NF-κB. At the same time, TNIP3 also decreased the expression of IL–17 in CD4 + T cells in spleen slices. On the contral, TNIP3 over expression increased the expression of FOXP3 in CD4+ T cells. These results further demonstrate the importance of TNIP3 in reducing inflammation and preventing UC.
CXCL1was originally found in melanoma and was also expressed in macrophages, neutrophils and epithelial cells. CXCL1 acts by specifically binding to its receptor, C-X-Cchemokine receptor type 2 (CXCR2).Recent studies have shown that the CXCL1/CXCR2 signaling pathway and chemotactic central granulocytes regulate the inflammatory response; moreover, the pathway causes tumor cell proliferation, angiogenesis, and lymph angiogenesis and promotes tumor invasion and vascular metastasis, which plays an important role in the occurrence and development of tumors, etc..Previous studies have shown that CXCL1 was concomitantly expressed in ulcerative colitis and decreased during treatment with topical corticosteroids.Recent research has shown that CXCL1 is critical for metastasis in colorectal cancer and pre-metastatic niche formation. The specific mechanism is that primary malignant cell secreted Vascular endothelial growth factor A(VEGF-A) stimulates tumor-associated macrophages to produce CXCL1, which recruits CXCR2-positive myeloid-derived suppressor cells to form a pre-metastatic niche to promote liver metastases.
SLC6A14, expressed on the apical membrane of epithelial cells, is a Na+/Cl--dependent neutral and cationic amino acid transporter.Due to its broad specificity and concentrative transport mechanisms, SLC6A14 is hypothesized to be involved in nutrient uptake.Moreover, changes of SLC6A1 expression are related to multiple diseases, such as obesity, cystic fibrosis, colitis, male infertility and various epithelial cancers[32–35]. Multiple sequencing or microarray studies have shown that SLC6A14 was upregulated in UC patients[5,8,36,58]. This indicates that the up-regulation of SLC6A14 is a common phenomenon in intestinal inflammation. SLC6A14 may be involved in colonic inflammation by regulating glutamine(a substrate for SLC6A14) and nitric oxide synthase 2 (coordinated upregulation with SLC6A14 in inflamed cells)[37,–38]. A recent study showed that abnormal permeability of the inner mucus was observed in some UC patients, with a significant reduction in SLC26A3, which provides the bicarbonate necessary for colonic mucosa formation, indicted that decreased mucus barrier in colon was an early event in ulcerative colitis pathogenesis. Whether SLC6A14 and SLC26A3 have synergistic effects in the pathogenesis of UC?  However, to date, the relationship between increased expression of SLC6A14 and inflammation remains unknown.
CD55, known as decay-accelerating factor, is a member of the regulators of complement activation(RCA) family. It is a major regulator of complement activation alternative and classical pathways and is expressed in all serum-exposed cells. CD55 physiologically acts as an inhibitor of the complement system but it is also broadly expressed in malignant tumors[42,43]. Previous studies have shown increased expression of CD55 in stools and colonic mucosa of disease activity in patients with UC[44,45].
The results of functional and pathway DEG enrichment in this study show thatthe biological functions involved in the pathogenesis of UC include the inflammatory response, innate immune response and chemotaxis, indicating that the pathogenesis of UC was multifactorial, involving epithelial barrier defects, genetic predisposition, environmental factors, and dysregulated immune responses. The six hub genes screened in this study are not only related to mucosal inflammation but they also accelerate the progression of colon cancer, so they should be given proper attention in the treatment of UC. Emerging studies have demonstrated that aberrant gut microbiota are involved in the development and progression of ulcerative colitis[46,47];therefore, aberrant gut microbiota may also participate in the pathogenesis of UC through the above pathways. Do abnormal gut microbiota affect the expression of host genes, or vice versa? The specific mechanism still needs to be explored.
Although we found six hub genes closely related to UC and confirmed the robustness of their diagnostic value, which may be useful for us to improve our understanding of the molecular mechanism of UC and as a potential prognostic and diagnostic biomarker, we still need further molecular biological experiments to confirm our hypothesis.