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

Abstract

Urethral stricture is related to scar tissue fibrosis, but its pathogenesis is still unclear. This study aims to explore the regulatory mechanism of circular RNA (circRNA) in the occurrence and development of urethral stricture. CircRNA microarray was employed to analyze circRNA expression profiles between human urethral scar tissue and normal urethral tissue. The results of circRNA microarray showed that there were 296 differentially expressed genes between urethral scar tissue and normal urethral tissue. The enrichment analysis of Kyoto encyclopedia of genes and genomes showed that these circRNAs were significantly correlated with ECM–receptor interaction. The first nine differentially expressed circRNA were selected to predict the circRNA–miRNA network. RT-qPCR results showed that circ_0047339 was upregulated considerably in urethral scar tissue. Urethral scar fibroblasts were isolated from human urethral scar tissue and cultured in vitro. After silencing circ_0047339, the proliferation of urethral scar cells decreased significantly, and the expressions of Collagen I (COL-1) and α-smooth muscle actin (α-SMA) also reduced. As a competing endogenous RNA, circ_0047339 could increase the expression of TSP-1 by competitively binding miR-4691-5p. In addition, miR-4691-5p mimic transfection could inhibit the proliferation of urethral scar fibroblasts and the presentation of thrombospondin-1 (TSP-1), α-SMA and COL-1, while circ_0047339 overexpression eliminated this inhibition. Our results showed that circ_0047339 might promote the growth and fibrosis of urethral scar fibroblasts through miR-4691-5p/TSP-1 axis, thus promoting the development of urethral stricture.

Overexpressed miR‐486 in bone marrow mesenchymal stem cells represses urethral fibrosis and targets Col13a1 in urethral stricture rats

“…They can interact with the 3′ untranslated regions (3′UTRs) of downstream target messenger RNAs (mRNAs), consequently destabilizing mRNAs or repressing translation 22 . Several miRNAs have been indicated to participate in regulating the progression of US, such as miR‐146a, miR‐4691‐5p, and let‐7i‐5p 4,23,24 . Intriguingly, a recent study demonstrated that miR‐486 was prominently downregulated after urethral injury 25 .…”

“… 22 Several miRNAs have been indicated to participate in regulating the progression of US, such as miR‐146a, miR‐4691‐5p, and let‐7i‐5p. 4 , 23 , 24 Intriguingly, a recent study demonstrated that miR‐486 was prominently downregulated after urethral injury. 25 Nonetheless, it is unclarified whether miR‐486 has an effect on the development of US.…”

Inhibition of urethral stricture by a catheter loaded with nanoparticle/ pirfenidone complexes

“…The formation and recurrence of urethral strictures are related to the formation of fibrosis in the healing process of the injured tissue, which is mainly related to the excessive deposition of extracellular matrix (ECM) in the submucosa of the urethra, an increase in collagen level, a change in the proportion of collagen types I and III, and an imbalance in ECM degradation (Hughes et al, 2020;Feng et al, 2021). Similar to many fibrosis-related diseases, abnormal expression of fibroblast genes in urethral tissues is believed to be a major cause of scarring (Ding et al, 2022). Transforming growth factor β1 (TGF-β1) is an effective chemokine of fibroblasts and an important mediator of fibrosis, as it induces the production and secretion of collagen by fibroblasts, thereby causing tissue fibrosis (Zhang et al, 2022).…”