miR-423-3p inhibits CTNNBIP1/WNT preventing hyperandrogenic PCOS

Abstract

Polycystic ovary syndrome (PCOS) lacks the generally accepted diagnostic biomarkers and targeted therapy. Increasing evidence indicates that microRNAs (miRNAs) play a crucial role in PCOS. Hereby, we tested the functional implications of a novel miRNA (miR-423-3p) as a mediator in the progress of hyperandrogenic PCOS, as well as its potential as a new serum biomarker and therapeutic target for the PCOS. We found significantly decreased miR-423-3p levels in serum, granulosa cells (hGCs), and follicular fluid (FF) of PCOS patients (n = 40) compared to healthy controls (n = 30), and this decrease corroborated in PCOS-like mouse models. The receiver operating characteristic (ROC) curve analysis for circulating miR-423-3p indicated high diagnostic potential as a biomarker, with an area under the curve (AUC) of 82%. miR-423-3p influenced human granulosa cell (KGN) proliferation by directly targeting CTNNBIP1 modulated WNT signaling pathway. We further proved as mechanistic role that the elevated dihydrotestosterone (DHT) inhibited the expression of miR-423-3p via the activation of the androgen receptor, and the overexpression of miR-423-3p normalized the function of androgen-induced GCs. While we overexpressed miR-423-3p, it counteracted androgen-induced dysfunction in GCs. Antiandrogen treatment restored the reproductive phenotypes in letrozole-induced PCOS-like mice and regulated miR-423-3p expression and its downstream effects. Ovarian intrabursal injection of miR-423-3p antagomir in wildtype (WT) mice induced PCOS-like phenotypes, further underscoring its functional role. Our results demonstrated that miR-423-3p emerged as a novel mediator in hyperandrogenic PCOS progression and it holds promise as both a diagnostic biomarker and a therapeutic target.

Keywords: Biomarker; Mir-423-3p; Polycystic ovary syndrome; Proliferation.