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

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.