Abstract
Circular RNAs (circRNAs) play a crucial role in the pathogenesis of various fibrotic diseases, but the potential biological function and expression profile of circRNAs in keloids remain unknown. Herein, microarray technology was applied to detect circRNA expression in four patient-derived keloid dermal fibroblasts (KDFs) and normal dermal fibroblasts (NDFs). A total of 327 differentially expressed (DE) circRNAs (fold change > 1.5, p < 0.05) were identified with 195 upregulated and 132 downregulated circRNAs. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses showed that the upregulated circRNAs were mainly enriched in the cytoskeleton and tight junctions, while the downregulated circRNAs were related to morphogenesis of the epithelium and axonal guidance. To explore the function of DE circRNAs, a circRNA-miRNA-mRNA network, including five circRNAs, nine miRNAs, and 235 correlated mRNAs, was constructed using bioinformatics analyses. The expression of five DE circRNAs was validated by qRT–PCR in 18 pairs of KDFs and NDFs, and hsa_circ_0006867 showed promising regulatory function in keloids in vitro. Silencing hsa_circ_00006867 suppressed the proliferation, migration, and invasion of keloid fibroblasts. RNA-binding protein immunoprecipitation (RIP) assays indicated that hsa_circ_00006867 may serve as a platform for miRNA binding to Argonaute (AGO) 2. In addition, hsa-miR-29a-5p may be a potential target miRNA of hsa_circ_00006867. Taken together, our research provided multiple novel clues to understand the pathophysiologic mechanism of keloids and identified hsa_circ_0006867 as a biomarker of keloids.
Highlights
Keloids are benign skin fibroproliferative tumors unique to humans characterized by aggressive fibroblast proliferation, excessive accumulation of extracellular matrix (ECM), long-term continuous fibrosis, and abnormal inflammatory stimuli (Yan et al, 2021; Zhang et al, 2021)
The results revealed that more than 80% of circRNAs were derived from exons of the host gene (Figure 2D)
Because circRNAs are mainly located in the cytoplasm and may act as sponges for miRNAs, we explored the subcellular localization of hsa_circ_0006867 in keloid dermal fibroblasts (KDFs) cells
Summary
Keloids are benign skin fibroproliferative tumors unique to humans characterized by aggressive fibroblast proliferation, excessive accumulation of extracellular matrix (ECM) (e.g., collagen I and III), long-term continuous fibrosis, and abnormal inflammatory stimuli (Yan et al, 2021; Zhang et al, 2021). Keloids show various cancer-like features, such as aggressive proliferation beyond the original boundary, lack of spontaneous regression, and vascularization ability (Huang and Ogawa, 2020). As a common clinically challenging disorder, keloid formation generally follows wounding, such as burns, surgery, laceration, or other damage to the dermis (Davies et al, 2021). Keloids can invade surrounding healthy skin out of the original wound, usually causing pain, severe itch, malformation, and even dysfunction, seriously affecting the physical and mental health of patients (Bijlard et al, 2017). Therapeutic options for keloids are few and ineffective with common recurrence and deformities posttherapy (e.g., surgery, drug injection, and perioperative radiation therapy) (Qu et al, 2013; Gold et al, 2020; Lv et al, 2020). There is an urgent need to explore and understand the aggressive progression of keloids to help identify novel effective treatment strategies and preventive methods
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