Role of metformin in functional endometrial hyperplasia and polycystic ovary syndrome involves the regulation of MEG3/miR-223/GLUT4 and SNHG20/miR-4486/GLUT4 signaling

Abstract

Metformin (MET) can effectively treat endometrial hyperplasia (EH), and the expression of glucose transporter type 4 insulin-responsive (GLU T4) is closely associated with the development of EH. The present study aimed to verify the effect of MET in functional EH and polycystic ovary syndrome (PCO S). H&E staining was performed to analyze the severity of EH, and immunohistochemistry was performed to evaluate the expression of GLU T4 in the endometrium of PCO S rats. Reverse transcription-quantitative PCR was used to calculate the expression of long non-coding (lnc)RNA -maternally expressed gene 3 (MEG3), lncRNA -small nucleolar RNA host gene 20 (SNHG20), GLU T4 mRNA, microRNA (miR)-223 and miR-4486. Sequence analysis and luciferase assays were performed to explore the regulatory relationship among certain lncRNA s, miRNA s and target genes. EH in PCO S rats was efficiently inhibited by MET administration. The increased expression of GLU T4 in PCO S rats was attenuated by MET treatment. Moreover, the expression levels of lncRNA -MEG3 and lncRNA -SNHG20 were significantly inhibited in the endometrium of PCO S rats. MET treatment also showed remarkable efficiency in restoring the expression of lncRNA -MEG3 and lncRNA -SNHG20. Meanwhile, the expression levels of miR-223 and miR-4486 were notably elevated in the endometrium of PCO S rats, while MET treatment reduced the expression of miR-223 and miR-4486 in PCO S rats. Furthermore, a luciferase assay confirmed the inhibitory relationship between miR-223 and lncRNA -MEG3/GLU T4 expression, as well as between miR-4486 and lncRNA -SNHG20/GLU T4 expression. GLU T4 knockdown restored the decreased viability of HCC -94 cells induced by overexpression of lncRNA -MEG3. To conclude, MET exhibited a therapeutic effect in the treatment of EH by modulating the lncRNA -MEG3/miR-223/GLU T4 and lncRNA -SNHG20/miR-4486/GLUT4 signaling pathways. This work provides mechanistic insight into the development of EH.