期刊
ANNALS OF TRANSLATIONAL MEDICINE
卷 9, 期 8, 页码 -出版社
AME PUBL CO
DOI: 10.21037/atm-21-596
关键词
Empty spiracles homeobox-2 (EMX2); homeobox protein A10 (HOXA10); implantation rate; beta3-integrin (ITG beta 3); microRNA-135a (miR-135a); progesterone elevation
资金
- National Key Research and Development Program [2018YFC1002106]
- Key projects of Basic and Applied Research in Yunnan Province [2018FA009]
- Open project of Yunnan Provincial Reproductive and Obstetrics and Gynecology Clinical Medicine Center [2019LCZXKF-SZ01]
- Program of Application and Fundamental Research of Joint Special project of Yunnan Provincial Science Technology Department & Kunming Medical University [2018FE001(-302)]
- National Natural Science Foundation of China [81660266]
- Yunnan Provincial Reproductive and Obstetrics and Gynecology Clinical Medicine Center [zx2019-01-01]
- [2017HB041]
This study revealed that high progesterone levels inhibit HOXA10 expression by promoting miR-135a, thereby affecting endometrial receptivity. This regulatory mechanism alters the expression of related genes, potentially leading to decreased implantation rates.
Background: Patients with elevated circulating progesterone concentrations on the day of the human chorionic gonadotropin (hCG) trigger had relatively low implantation rates during assisted reproductive treatments. In this study, we assess the hypothesis that different concentrations of progesterone regulate the expression of homeobox protein A10 (HOXA10) and its downstream genes through miRNA-135a. Methods: Micro RNA-135a (miR-135a), HOXA10, beta3-integrin (ITG beta 3), and empty spiracles homeobox-2 (EMX2) expression levels in endometrial tissues from patients with elevated progesterone were measured. To determine the threshold of progesterone level which can impair implantation, Ishikawa cells were used to determine the expression of the aforementioned 4 genes after exposure to 5 graded concentrations of progesterone. The dual-luciferase reporter assay was used to verify whether miR-135a regulated the expression of HOXA10. Furthermore, the effects of HOXA10 on the expression of key endometrial receptivity genes ITG beta 3 and EMX2 were confirmed. Results: High progesterone levels promoted miR-135a expression in vivo, and miR-135a bound to the 3'-untranslated region (3'-UTR) of HOXA10 mRNA to inhibit HOXA10 expression. Reduction of HOXA10 promoted EMX2 expression and inhibited ITG-3 production. Progesterone promoted the expression of HOXA10 in vitro at low concentrations. However, when the concentration was greater than 10(-7) ng/mL, progesterone inhibited HOXA10 by promoting miR-135a expression, thereby altering the expression of related genes and affecting endometrial receptivity. Conclusions: In vitro, the trend in miR-135a expression (which first decreased and then increased) was in direct contrast to that of HOXA10 expression (which first increased and then decreased) as progesterone levels increased. The key factors regulating endometrial receptivity included ITG beta 3 and EMX2, which were confirmed to be regulated by HOXA10. High progesterone levels affected miR-135a expression, and miR-135a inhibited HOXA10 expression, thereby affecting endometrial receptivity.
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