# SOX9 regulates epithelial‐mesenchymal transformation by mediating the Wnt/β‐catenin signaling pathway in hypospadias

## TL;DR

This study shows that reduced SOX9 levels disrupt Wnt signaling and epithelial-mesenchymal transition, contributing to hypospadias development.

## Contribution

The novel finding is that SOX9 mediates Wnt/β-catenin signaling and EMT in hypospadias.

## Key findings

- SOX9, Wnt signaling, and EMT mesenchymal markers were reduced in hypospadias tissues.
- SOX9 inhibition in fibroblasts mimicked hypospadias-like changes.
- Down-regulated SOX9 disrupts urethral development via Wnt/β-catenin and EMT pathways.

## Abstract

The transcription factor SOX9 is crucial in the development and differentiation of various tissues and cells. However, the roles of SOX9‐dependent genes and pathways in normal urethral development and the mechanism of hypospadias are unclear. This study collected 15 foreskin tissue specimens from patients who underwent hypospadias repair surgery and compared them to normal foreskin tissue specimens obtained during circumcision. The expression levels of SOX9, WNT signaling pathway markers, and epithelial‐mesenchymal transition (EMT) markers were analyzed in both groups. It was found that mRNA and protein levels of SOX9, WNT signaling pathway, and EMT mesenchymal markers were significantly reduced in the hypospadias group compared to the normal foreskin group. In contrast, mRNA and protein levels of epithelial markers were significantly increased in the hypospadias group. Immunofluorescence confirmed the decrease in SOX9 expression. Experiments using siRNA to inhibit SOX9 expression in foreskin fibroblasts yielded similar results to the hypospadias group. The findings suggest that down‐regulation of SOX9 expression may contribute to the development of hypospadias by down‐regulating the WNT pathway and inhibiting EMT. These findings provide new insights into the embryonic development of the urethra.

The inhibition of SOX9 in mesenchymal cell may mediates the aberrant expression of the Wnt/β‐catenin signaling pathway EMT process, leading to the development of urethral hypospadias.