AI Article Synopsis

  • Dysregulated apoptosis of penile mesenchymal cells is linked to hypospadias, with androgen receptors (AR) playing a crucial role in regulating cell behavior; however, the mechanisms involving AR are not well understood.
  • Research indicates that the circRNA hsa_circ_0000417, which is less present in hypospadias, functions as a competitive endogenous RNA (ceRNA) for miR-6756-5p and influences the PI3K/AKT pathway, impacting cell proliferation and apoptosis.
  • The study found that knocking down hsa_circ_0000417 leads to increased HFF-1 cell proliferation and decreased apoptosis by modulating the levels of miR-6756-5p

Article Abstract

Background: Dysregulated apoptosis of penile mesenchymal cells during male urethragenesis has been previously demonstrated to underly hypospadiac urethral closure failure, and androgen receptor (AR) has been shown to play a central role in regulating penile mesenchyme cell proliferation and survival. However, the regulatory mechanisms upstream and downstream of AR remain poorly understood. Our clinical data and bioinformatics analysis previously indicated that hsa_circ_0000417, a circRNA significantly downregulated in hypospadias preputial specimens, may act as a ceRNA for AR via sequestering hsa_miR-6756-5p, and that the biological functions of hsa_circ_0000417 may significantly involve the PI3K/AKT pathway. In this study, we employed human foreskin fibroblasts (HFF-1) to experimentally validate this putative hsa_circ_0000417/miR-6756-5p/AR axis and its impact on penile mesenchymal cell proliferation and apoptosis.

Method And Results: We showed that hsa_circ_0000417 knockdown significantly promoted proliferation and suppressed apoptosis of HFF-1 cells. Mechanistically, hsa_circ_0000417 functioned as a molecular sponge for miR-6756-5p in HFF-1 cells and relieved the latter's translational repression on AR mRNA, leading to decreased AKT activation and increased expression of pro-apoptotic proteins BAX and cleaved-caspase 9. Conversely, elevated levels of miR-6756-5p resulted in diminished AR expression concomitant with enhanced AKT activation and HFF-1 cell proliferation.

Conclusions: Collectively, our data describe for the first time a circRNA-mediated post-transcriptional regulatory mechanism of AR and its functional consequences in penile mesenchymal cells in the context of hypospadias. These findings may contribute to advancing our current understanding of the roles of AR and mesenchymal cell fate decisions during penile morphogenesis.

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http://dx.doi.org/10.1007/s11033-023-08628-6DOI Listing

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