Abstract
Due to many inconsistencies in differentially expressed genes (DEGs) related to genomic expression changes during keloid formation and a lack of satisfactory prevention and treatment methods for this disease, the critical biomarkers related to inflammation and the immune response affecting keloid formation should be systematically clarified. Normal skin/keloid scar tissue-derived fibroblast genome expression data sets were obtained from the Gene Expression Omnibus (GEO) and ArrayExpress databases. Hub genes have a high degree of connectivity and gene function aggregation in the integration network. The hub DEGs were screened by gene-related protein–protein interactions (PPIs), and their biological processes and signaling pathways were annotated to identify critical biomarkers. Finally, eighty-one hub DEGs were selected for further analysis, and some noteworthy signaling pathways and genes were found to be closely related to keloid fibrosis. For example, IL17RA is involved in IL-17 signal transduction, TIMP2 and MMP14 activate extracellular matrix metalloproteinases, and TNC, ITGB2, and ITGA4 interact with cell surface integrins. Furthermore, changes in local immune cell activity in keloid tissue were detected by DEG expression, immune cell infiltration, and mass CyTOF analyses. The results showed that CD4+ T cells, CD8+ T cells and NK cells were abnormal in keloid tissue compared with normal skin tissue. These findings not only support the key roles of fibrosis-related pathways, immune cells and critical genes in the pathogenesis of keloids but also expand our understanding of targets that may be useful for the treatment of fibrotic diseases.
Highlights
A keloma, known as a keloid, is a benign dermal collagen tumour caused by chronic skin tissue lesions and inflammation that mainly forms due to collagen and extracellular matrix (ECM) deposition [1, 2]
Gene expression differences in keloid fibroblasts in each study group were displayed in Table 2, but the expression difference in each gene was heterogeneous among the different groups, necessitating examination of the discrepancies in the expression of important genes
The results showed that these five datasets had only three common genes: BPGM, SKAP2, and NEO1 (Supplementary Figure S1A)
Summary
A keloma, known as a keloid, is a benign dermal collagen tumour caused by chronic skin tissue lesions and inflammation that mainly forms due to collagen and extracellular matrix (ECM) deposition [1, 2]. Some studies have used microarray technology to compare fibroblast cultures of normal skin/keloid scar tissues. These genome expression studies have found many genes and pathways related to keloid fibrosis diseases, such as hypoxia inducible factor-1a [6], insulin-like growth factor binding protein-3 and the Wnt signaling pathway [7]. Microarray studies have identified common patterns of gene expression changes in autoimmune diseases [8] These studies all included small samples, and considerable heterogeneity was identified between the results for gene expression differences. To accurately screen the key genes and pathways in keloid formation and develop procedures to alter genes related to fibroblasts in lesions, genome aggregation analysis was applied to improve statistical analysis capabilities and the credibility of the results. Five gene expression profiles including 29 keloid and 24 normal specimen tissues, were acquired from the public Gene Expression Omnibus (GEO) and ArrayExpress databases, and the genome-wide expression profiles of normal skin/keloid scar fibroblasts were comprehensively analyzed
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