Expression of Rab25 is down-regulated in the foreskin of children with hypospadias

Abstract

Background: Hypospadias, a congenital malformation of the penis, is one of the newborns' most common developmental defects. The incidence of hypospadias is increasing yearly, and its pathogenesis is closely related to genetic susceptibility and environmental exposure to endocrine disruptors. Exploring the hypospadias' key molecular regulatory mechanism is crucial to reducing its incidence.

Objective: To examine the differential expression of Rab25 in hypospadias and normal penile tissue and to identify whether it is a candidate gene for exploring the mechanism of hypospadias.

Study design: This study included 18 children aged 1-6 years undergoing hypospadias repair surgery at the Children's Hospital of Chongqing Medical University, and foreskin samples were collected. Children diagnosed with cryptorchidism, intersex status, or endocrine abnormalities were excluded from this study. Another 18 children aged 3-8 years with phimosis were included in the control group. The specimens were used for immunohistochemistry, western blotting, immunofluorescence, and polymerase chain reaction to assess the expression of Rab25.

Results: Rab25 protein expression was lower in the hypospadias group than in the control group [ (2.101 ± 0.1845), (0.7506 ± 0.1779), p = 0.0008 < 0.05). The hypospadias group showed decreased expression of Rab25 protein in the epithelial cell layer. Rab25 mRNA levels were downregulated in the foreskin of children with hypospadias compared with controls [(1.697 ± 0.2005), (0.7687 ± 0.2130), p = 0.0053 < 0.05)].

Discussion: Rab25 mRNA and protein expressions in the hypospadias group were significantly downregulated compared with the control group. This was consistent with the results of single-cell sequencing of fetal mice reproductive nodules at 15.5 days of gestation (Zhang Z, Liu Z, Zhang Q, et al., unpublished observations). Our study represents the first report of abnormal Rab25 expression in the foreskin tissue of patients with hypospadias. More detailed research on the relationship between Rab25 and urethral development could be conducted to reveal the molecular mechanism of hypospadias.

Conclusion: The expression of Rab25 in foreskin tissue was lower in the hypospadias group than in the control group. Rab25 is involved in the formation of the urethral seam and the occurrence of hypospadias. The potential mechanism by which Rab25 affects the canalization of the urethral plate needs to be further investigated.

Keywords: Epidermal growth factor receptor; Epithelial-mesenchymal transition; Hypospadias; Rab25; β1-integrin.