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Abstract
Keloids are a type of aberrant skin scarring characterized by excessive accumulation of collagen and extracellular matrix (ECM), arising from uncontrolled wound healing responses. While typically non-pathogenic, keloids are occasionally regarded as a form of benign tumor. CR6-interacting factor 1 (CRIF1) is a well-known CR6/GADD45-interacting protein, that has both nuclear and mitochondrial functions, and also exerts regulatory effects on cell growth and apoptosis. In this study, cell proliferation, cell migration, collagen production and TGF-β signaling was compared between normal fibroblasts (NFs) and keloid fibroblasts (KFs). Subsequently, the effects of CRIF1 deficiency were investigated in both NFs and KFs. Cell proliferation, cell migration, collagen production and protein expressions of TGF-β, phosphorylation of Smad2 and Smad3 were all found to be higher in KFs compared to NFs. CRIF1 deficiency in NFs and KFs inhibited cell proliferation, migration, and collagen production. In addition, phosphorylation of Smad2 and Smad3, which are transcription factors of collagen, was decreased. In contrast, mRNA expression levels of Smad7 and SMURF2, two important inhibitory proteins of Smad2/3, were increased, suggesting that CRIF1 may regulate collagen production. CRIF1 deficiency decreases the proliferation and migration of KFs, thereby inhibiting their overgrowth via the transforming growth factor-β (TGF-β)/Smad pathway. CRIF1 may therefore represent a potential therapeutic target in keloid pathogenesis.
Highlights
Keloid disease, or keloid scarring, is a condition in which pathological scar tissue grows aggressively beyond the boundary of the original wound
Keloids arise as a result of excessive wound healing after skin damage, characterized by increases in cell proliferation, migration, inflammation, and collagen production, and excessive extracellular matrix (ECM) synthesis[9]
Previous reports have suggested that the anti-apoptotic effects of keloid fibroblasts (KFs) in combination with increased proliferation and collagen deposition were higher than seen in normal fibroblasts (NFs), with ~ 15% of genes being significantly upregulated in KFs21,22
Summary
Keloid scarring, is a condition in which pathological scar tissue grows aggressively beyond the boundary of the original wound. The primary driver of keloid formation is an abnormal elevation of fibroblast activity, leading to a greater amount of connective tissue proliferation and hyaline degeneration[2]. In addition to increased cytokine production, KFs exhibit increased transcription of numerous cytokine receptors relative to NFs, leading to excessive synthesis of proteoglycans, collagen, and other extracellular matrix (ECM) components. Keloids exhibit increased levels of acid-soluble collagen, proteoglycans, and water relative to both normal and hypertrophic scars[9] Taken together, these findings indicate that keloids can be characterized in terms of overgrowth of fibroblasts, migration outside of the normal wound region, and excessive synthesis of ECM. The aim of our study was to downregulate CRIF1 expression in NFs and KFs, to assess its effects on cell proliferation, migration, and collagen production. We suggest that suppression of CRIF1 may be an important factor in keloid treatment
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