microRNA-194 is increased in polycystic ovary syndrome granulosa cell and induce KGN cells apoptosis by direct targeting heparin-binding EGF-like growth factor

Abstract

Background Polycystic ovary syndrome (PCOS) is an endocrine-related follicular developmental disorder that affects 50 %-70 % of reproductive-aged women diagnosed with ovulation-related infertility. Abnormal proliferation and apoptosis of granulosa cells (GCs) are thought to be the critical factors leading to abnormal maturation of follicles. It has been shown that microRNAs (miRNAs) exert a significant influence in the pathogenesis of PCOS; however, the relationship between miRNA, PCOS, and GC apoptosis is not entirely understood. Methods To clarify the effect of miR-194 in PCOS, CCK-8, Ki67 staining, AO/EB, and flow cytometry assays were used to assess cell growth, proliferation, and apoptosis in KGN cells, which were artificially stimulated to overexpress miR-194. Luciferase reporter assays and rescue experiments were used to elucidate the mechanism underlying miR-194 in PCOS. Results miR-194 expression was significantly up-regulated in rat models of PCOS and the ovarian GCs of PCOS patients. miR-194 suppression promoted KGN cell growth and proliferation. miR-194 overexpression also induced cell apoptosis, while miR-194 downregulation had an opposite effect. Furthermore, up-regulating heparin-binding EGF-like growth factor (HB-EGF) expression rescued the pro-apoptotic effects of miR-194 upregulation on KGN cells. Conclusions miR-194 is increased in PCOS granulosa cell and may function as a novel biomarker and therapeutic target for KGN cells via HB-EGF regulation.

HB-EGF upregulates StAR expression and stimulates progesterone production through ERK1/2 signaling in human granulosa-lutein cells

“…The results are expressed as the mean ± SEM of at least three independent experiments. Values that are statistically different from one another (p < 0. and in the ovaries of PCOS rats [32]. Our results showed that StAR expression was upregulated by HB-EGF in hGL cells.…”

“…Therefore, future studies will need to confirm the protein levels of HB-EGF in human follicular fluid. The mRNA levels of HB-EGF are downregulated in the granulosa cells of PCOS patients and in the ovaries of PCOS rats [ 32 ]. Our results showed that StAR expression was upregulated by HB-EGF in hGL cells.…”

HB-EGF induces mitochondrial dysfunction via estrogen hypersecretion in granulosa cells dependent on cAMP-PKA-JNK/ERK-Ca2+-FOXO1 pathway

“…The present study exhibited the elevation of HB-EGF level in follicular fluid from PCOS women. Meanwhile, aberrant HB-EGF expression was also noted in PCOS patient GCs [18]. Together these observations imply a potential involvement of HB-EGF in PCOS etiology.…”

Role of EGFR expressed on the granulosa cells in the pathogenesis of polycystic ovarian syndrome

“…For example, Gao et al showed that the level of serum EFG in the abortion PCOS patients was higher than that in the successful delivery PCOS patients, moreover, EFG was an independent factor which affecting and positively correlated with the pregnancy outcome of PCOS patients (26). Mechanistically, in a recent study by Wu and colleagues, they found that high expression of microRNA-194 in granulosa cell of PCOS patients could induce KGN cells apoptosis by direct targeting heparinbinding EGF-like growth factor (27). More recently, Huang and co-workers indicated that heparin-binding-EGF might induce mitochondrial dysfunction and granulosa cells apoptosis through advancing estrogen hypersecretion dependent on c A M P -P K A -J N K/ E R K -C a 2 + -FOXO1 pathway (2 8 ).…”