SRSFs mediate the function of AR in the ovarian granulosa cells of patients with PCOS

Abstract

Ovarian hyperandrogenism is one of the characteristics of polycystic ovary syndrome (PCOS) and androgen receptor (AR) in ovarian granulosa cells (GCs) functions as an important element to the accumulation of androgens. This study verified the existence of alternative splicing variant of AR (AR-SVs) in the GCs of PCOS patients and found that the function of AR decreased significantly in the presence of AR-SVs. And compared to the normal individuals, the expression of Serine/arginine-rich splicing factor 2(SRSF2) was higher and the expression of SRSF3 was lower in the GCs of patients with AR-SVs. More importantly, we found that the expression of SRSF2 was inhibited and that the expression of AR was decreased after the successful upregulation of miRNA-183, and testostrone (T) concentrations in the culture medium were increased. The results also showed that the expression of SRSF3 decreased when miRNA-124 was successfully upregulated, while the expression of AR significantly increased; however, the function of AR was also inhibited when T concentration in the culture medium was increased. This study has proved that SRSFs are regulated by corresponding miRNAs, and the altered expression of SRSFs interferenced the alternative splicing process of AR and ultimately decreased the function of AR, leading to the accumulation of androgens in the ovary.

Curcumin Inhibits Hyperandrogen-Induced IRE1α-XBP1 Pathway Activation by Activating the PI3K/AKT Signaling in Ovarian Granulosa Cells of PCOS Model Rats

“…In our study, DHEA was continuously injected subcutaneously into adolescent rats for 35 days. The rats lost their regular estrus Research has shown that androgen receptor (AR) mRNA expression was significantly higher in the GCs of patients with higher androgen levels in the follicular fluid than in those of control patients [32]. This suggests that the increase in AR expression did not enhance the function of transforming androgens.…”

Androgen excess: a hallmark of polycystic ovary syndrome

“…The former is caused by the insertion of 69 base pairs between exons 2 and 3, whereas the latter lacks exon 3. In addition, patients who carry Ins-AR are positively correlated with high AMH levels; however, although AR mRNA is elevated in all groups, no significant difference in the abundance of AR mRNA was observed between the AR-SV and wild-type AR (WT-AR) groups ( 107 ). This could be explained by alterations in the AR DBD structure of the two isoforms, which then affect the transcription of genes regulating follicular growth and steroidogenesis.…”

“…This may explain why patients with the Del-AR variant exhibited a milder PCOS phenotype. Moreover, serine/arginine-rich splicing factors (SRSF), especially SRSF2 and SRSF3, which are regulated by miRNA183 and miRNA124, respectively, participate in the formation of ASVs ( 107 ). Xue et al.…”

Posttranslational modifications in pathogenesis of PCOS

“…Recent studies have shown that the core etiology and major endocrine characteristics of PCOS are hyperandrogenemia and insulin resistance (15). Androgen receptor (AR) in ovarian granulosa cells (GCs) is an important factor in androgen accumulation (16). In addition to steroid regulation, various kinases alter AR activity by regulating phosphorylation at serine, threonine, and tyrosine residues (17).…”