Aberrant activation of the Hedgehog signaling pathway in granulosa cells from patients with polycystic ovary syndrome

Abstract

The molecular mechanism that triggers polycystic ovary syndrome (PCOS) is mysterious. Abnormal development of ovarian granulosa cells (GCs) is one of the causes of PCOS. Herein, our study was carried out using RNA-seq to detect the different gene expression levels in ovarian GCs between three patients with PCOS and four normal controls. To verify the RNA-seq data, GCs from 22 patients with PCOS and 21 controls with normal ovulation were collected to perform the RT-PCR analysis. Hedgehog signaling pathway (Hh) members, Ihh and Ptch2 were abnormally highly expressed in the PCOS tissue (PT). The qPCR also indicated that the expression levels of Hh signaling pathway downstream members, Ptch1, Gli1, and Gli2 in the PT were significantly higher than those in the normal tissue (NT). Besides, the expression of TNF-α mRNA in PCOS patients was higher than that in the control group. Through the chromatin immunoprecipitation assay (ChIP), we found that the Gli1-IP-DNA enriched from the granular cells of PCOS patients was higher than that of the control group. Finally, the Hh signaling pathway inhibitor, cyclopamine, can decrease the apoptosis of PCOS ovarian granulosa cells. These results suggest that abnormal activation of Hh signaling pathway, especially Ihh signal, may have a profound influence on PCOS.

CPEB1 induces autophagy and promotes apoptosis in ovarian granulosa cells of polycystic ovary syndrome

“…The high androgen environment may be the key factor causing abnormal development of GCs and ovulation abnormalities in PCOS. During this process, GCs exhibit high levels of apoptosis and inflammation (Li et al, 2021). Therefore, this study used DHEA and testosterone to establish PCOS rats and injured GC models.…”

Signaling pathways and targeted therapeutic strategies for polycystic ovary syndrome

“…Li observed higher levels of Ihh and Ptch2 in PCOS patients based on RT-PCR analysis when compared to a control group, indicating over-expression of the Hh signaling pathway in PCOS patients. This is also related to the aberrant follicular growth observed in PCOS patients (314). Yi et al have demonstrated that overactivation of the Hedgehog signaling pathway in the ovary inhibits ovulation.…”

“…The Hh signaling pathway inhibitor cyclopamine can decrease apoptosis of ovarian granulosa cells in PCOS (314). Conversely, another study has revealed that administration of cyclopamine partially counteracts the protective effects of GIMAP7 knockout on rats with PCOS with increased ROS levels (318).…”

Current Advances in Cellular Approaches for Pathophysiology and Treatment of Polycystic Ovary Syndrome

“…Therefore, successfully isolating and purifying abundant levels of high-quality GCs from the follicular fluid is crucial for PCOS research [34,35]. As shown in Table 2, several human GC isolation techniques have been described in the literature, enabling us to investigate the development mechanisms of PCOS, including proliferation, apoptosis, insulin resistance (IR), and oxidative stress (OS) [36][37][38][39][40][41][42][43][44][45][46][47][48][49]. Hyperandrogenism is also a prominent feature of PCOS, characterized by excessive production of ∆4 steroids such as androstenedione (A4) and testosterone, which can lead to anovulation, oligomenorrhea, and infertility [50].…”

“…Dysregulated miRNAs, including miR-33b, miR-142, miR-125b, miR-203a, and miR-423, have been identified in GCs from PCOS patients and may be involved in regulating the TGFβ-signaling pathway, promoting cell proliferation, and repressing apoptosis [37,40,41]. Furthermore, expression of components in the hedgehog (Hh) signaling pathway has been observed in the GCs of PCOS patients as well as in ovarian tissues in mice [49,113]. Inhibiting the Hh signaling pathway has been shown to decrease GC apoptosis in PCOS, indicating that aberrant activation of the Hh signaling pathway is related to abnormal follicular development in PCOS patients [49].…”