Metformin Regulates Key MicroRNAs to Improve Endometrial Receptivity Through Increasing Implantation Marker Gene Express
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Reproductive Sciences 1-10 ยช The Author(s) 2018 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/1933719118820466 journals.sagepub.com/home/rsx
Jun Zhai, PhD1, Gui-Dong Yao, PhD1, Jing-Yuan Wang, MD1, Qing-Ling Yang, PhD1, Liang Wu, PhD1, Zi-Yin Chang, MS1, and Ying-Pu Sun, PhD1
Abstract To some extent, the use of metformin may improve endometrial receptivity and pregnancy outcomes of women with polycystic ovarian syndrome (PCOS) undergoing in vitro fertilization/intracytoplasmic sperm injection. However, the mechanism is not wellknown. The endometrium of metformin-treated group (metformin-treated patients with PCOS) and the control group (nonmetformin-treated patients with PCOS) were analyzed for the expression of homeobox A10 (HOXA10) and integrin beta-3 (ITGB3) and differential micro RNA (miRNA) expression profiles. On this basis, miRDB and Target Scan databases were used to predict and screen out that miR-491-3p and miR-1910-3p may target HOXA10 and ITGB3. Furthermore, we verified the effects of metformin on the expression of HOXA10 and ITGB3, and regulatory effects of miR-1910-3p and miR-491-3p on HOXA10 and ITGB3 using Ishikawa cell line. Metformin induced a significant dose-dependent upregulation of HOXA10 and ITGB3. The results from the microarray analyses showed there were 40 differentially expressed miRNAs between the 2 groups. Among them, miR1910-3p and miR-491-3p were the 2 significantly downregulated miRNAs. Bioinformatics prediction indicated that HOXA10 and ITGB3 are potential target genes for miR-1910-3p and miR-491-3p. In Ishikawa cells transfected with miR-491-3p mimics, the expression of HOXA10 and ITGB3 on both messenger RNA (mRNA) and protein level were lower than those in control group (P < .001). Also, the expression of HOXA10 mRNA and protein was lower in Ishikawa cells transfected with miR-1910-3p mimics (P < .001). However, no significant changes in ITGB3 levels were observed in cells transfected with miR-1910-3p mimics (P > .05). Metformin likely improves endometrial receptivity through downregulating the expression of miR-491-3p and miR-1910-3p, thereby increasing the expression of HOXA10 and ITGB3 in the endometrium of PCOS women. Keywords metformin, polycystic ovarian syndrome, in vitro fertilization-embryo transfer (IVF-ET), endometrium tissue, microRNA
Introduction Polycystic ovarian syndrome (PCOS) is characterized by reproductive endocrine disorders (hyperandrogenism and elevated luteinizing hormone [LH] to follicle-stimulating hormone [FSH] ratios) and a series of metabolic disorders, with incidences between 6% and 21% in reproductive age women.1,2 Polycystic ovarian syndrome seriously affects the fertility of women despite unknown etiology.3 Approximately 50% of patients with PCOS exhibits insulin resistance, impaired glucose tolerance, and dyslipidemia.4 It is generally accepted that insulin resistance and secondary hyperinsulinemia have a pivotal role in the pathophysiology of PCOS.5,6 The endocrine and metabolic abnormalities in patients with PCOS als
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