circNRIP1 facilitates keloid progression via FXR1‑mediated upregulation of miR‑503‑3p and miR‑503‑5p

Abstract

circular nuclear receptor interacting protein 1 (circNRIP1) is implicated in tumor initiation and progression; however, the underlying mechanism of keloid progression is unclear. To the best of our knowledge, the present study is the first to characterize the contribution of circNRIP1 to keloid progression and evaluate the potential underlying molecular mechanisms using keloid-derived fibroblasts. The expression profile of circNRIP1 was confirmed in keloid tissue. The contribution of circNRIP1 to keloid progression was investigated via loss-of-function assays. Furthermore, the molecular mechanism by which circNRIP1 contributes to pre-microRNA (miR)-503 maturation through blocking Fbxo4-mediated Fragile-X mental retardation 1 (FXR1) ubiquitination was verified. Finally, the biological functions of FXR1, miR-503-3p, and miR-503-5p in keloid-derived fibroblast proliferation, apoptosis and extracellular matrix accumulation were confirmed. circNRIP1 was highly expressed in keloid tissue and keloid-derived fibroblasts. Functional analysis showed that circNRIP1 knockdown successfully blocked the proliferation and expression of extracellular matrix-associated proteins while increasing the rate of apoptosis in keloid-derived fibroblasts. Mechanistically, circNRIP1 maintained FXR1 stability by impeding Fbxo4-mediated FXR1 ubiquitination and degradation. Additionally, FXR1 increased the abundance of miR-503-3p and miR-503-5p by contributing to pre-miR-503 maturation. Knockdown of FXR1, miR-503-3p and miR-503-5p also inhibited proliferation and extracellular matrix accumulation in keloid-derived fibroblasts and increased levels of cell apoptosis. collectively, the present study confirmed that circNRIP1 contributed to pre-miR-503 maturation via blocking Fbxo4-mediated FXR1 ubiquitination and degradation, which facilitates keloid progression. These results indicate that circNRIP1 has potential as a novel therapeutic target for the control and/or treatment of keloids.

Advances in the pathogenesis and clinical application prospects of tumor biomolecules in keloid

“…Likewise, circNRIP1 is involved in the proliferation and apoptosis of tumor cells in breast and gastric cancers and is highly expressed in human keloids. circNRIP1 blocks the ubiquitination of FXR1, a key molecule of miR-503 maturation, by binding to it [ 172 ]. The elevation of circNRIP1 is ultimately accompanied by an increase in miR-503, which has been shown to escalate extracellular matrix deposition and promote cell division and differentiation ( Table 5 ).…”

Circ_0047339 promotes the activation of fibroblasts and affects the development of urethral stricture by targeting the miR-4691-5p/TSP-1 axis

“…The existing literature mainly focuses on renal fibrosis 20 , 27 . Other studies have found that circRNA is related to the mechanism of keloid formation 29 – 31 . Our study used gene chip technology to analyze the differentially expressed circRNA in urethral scar tissue.…”

Circular RNA hsa_circ_0057452 facilitates keloid progression by targeting the microRNA-1225-3p/AF4/FMR2 family member 4 axis

“…For example, circ_101238 expression levels are upregulated in keloid tissues, stimulating cell growth by activating KF proliferation, while inhibiting apoptosis [ 30 ]. circNRIP1 knockdown successfully blocks the proliferation of KFs and expression of extracellular matrix proteins, while increasing the apoptosis rate [ 31 ]. In this study, we confirmed for the first time the effects of hsa_circ_0057452 on KF viability, migration, and apoptosis, and explored the specific mechanism by which hsa_circ_0057452 regulates keloid progression.…”