Keloid Biomarkers and Their Correlation With Immune Infiltration

Abstract

Objective: This work aimed to verify the candidate biomarkers for keloid disorder (KD), and analyze the role of immune cell infiltration (ICI) in the pathology of keloid disorder.Methods: The keloid-related datasets (GSE44270 and GSE145725) were retrieved from the Gene Expression Omnibus (GEO). Then, differential expressed genes (DEGs) were identified by using the “limma” R package. Support vector machine-recursive feature elimination (SVM-RFE) and LASSO logistic regression were utilized for screening candidate biomarkers of KD. The receiver operating characteristic (ROC) curve was used to evaluate the diagnostic power of candidate biomarkers. The candidate biomarkers were further verified through qRT-PCR of keloid lesions and the matched healthy skin tissue collected from eight cases. In addition, ICI in keloid lesions was estimated through single-sample gene-set enrichment analysis (ssGSEA). Finally, the potential drugs to the treatment of KD were predicted in the Connectivity Map Database (CMAP).Results: A total of 406 DEGs were identified between keloid lesion and healthy skin samples. Among them, STC2 (AUC = 0.919), SDC4 (AUC = 0.970), DAAM1 (AUC = 0.966), and NOX4 (AUC = 0.949) were identified as potential biomarkers through the SVM-RFE, LASSO analysis and ROC analysis. The differential expressions of SDC4, DAAM1, and NOX4 were further verified in collected eight samples by qRT-PCR experiment. ICI analysis result showed a positive correlation of DAAM1 expression with monocytes and mast cells, SDC4 with effector memory CD4+ T cells, STC2 with T follicular helper cells, and NOX4 with central memory CD8+ T cells. Finally, a total of 13 candidate small molecule drugs were predicted for keloids treatment in CMAP drug database.Conclusion: We identified four genes that may serve as potential biomarkers for KD development and revealed that ICI might play a critical role in the pathogenesis of KD.

IFNγ regulates ferroptosis in KFs by inhibiting the expression of SPOCD1 through DNMT3A

“…Previous studies have indicated that the IFNγ produced by CD8 + T cells appears to improve antitumor responses by enhancing tumor sensitivity to ferroptosis [47,48]. And the development of keloid is also influenced by the modulation of immune responses [49][50][51]. Chen et al used flow cytometry to analyze the subsets and functions of cells in keloid and found that the number of effector memory CD8 + T cells and CD103 + CD8 + resident memory T cells was increased in keloid tissue [52].…”

Identifification and validation of ferroptosis signatures and immune infifiltration characteristics associated with intervertebral disc degeneration

“…Xiao et al (Xiao et al, 2022) confirmed that NOX4, as one of the genes associated with ferroptosis, is an effective biomarker for the development of gastric cancer. In addition, NOX4 is also one of the marker genes of immune infiltration, and is highly correlated with the prediction of gastric cancer immunotherapy (Xin et al, 2022), the pathogenesis of keloid disorder (Yin et al, 2022), and the clinical outcome of colon cancer (Yang et al, 2020). Our results also confirm that NOX4 is positively correlated with the proportion of multiple immune cells, suggesting that NOX4 is very likely to accelerate the immune process of disc degeneration by promoting immune infiltration, but this needs to be verified by further molecular biology experiments.…”

An updated review of the immunological mechanisms of keloid scars

“…Interestingly, there appeared to be a concomitant excess of regulatory cell types and cytokines ( 64 , 65 ). Study of keloid histology demonstrated altered expression of ECM molecules with increased type I/III collagen ratio, and a hypercellular dermis with increased numbers of fibroblasts, mast cells and macrophages, as well as varying presence of lymphocytes ( 1 , 36 , 64 , 66 – 75 ). Keloid tissue also harbored a higher percentage of mesenchymal stem cells, and the amount of which was found to be correlated with disease recurrence ( 76 ).…”

“…The concept of keloid microenvironment has been frequently evoked to describe the complex cellular and molecular interplay that gives rise to and sustains keloidogenesis. Recent technologies, such as identification of differentially expressed genes via examination of RNA sequencing data sets ( 74 , 75 , 78 – 80 ), have led to more extensive analysis of keloid tissue. A skewed T helper (Th) 2 phenotype was recently characterized ( 81 – 85 ), along with a potential co-susceptibility of keloids and atopic dermatitis ( 6 , 12 , 86 ).…”