title: MicroRNA-145 Negatively Regulates Cell Proliferation Through Targeting IRS1 in Isolated Ovarian Granulosa Cells From Patients With Polycystic Ovary Syndrome.
abstract: Polycystic ovary syndrome (PCOS) is a complex, heterogeneous endocrine and metabolic disorder affecting 5% to 10% of reproductive-age women. A high rate of granulosa cell (GC) proliferation contributes to the abnormal folliculogenesis in patients with PCOS. Evidence has proved that dysregulation of microRNAs is involved in the pathogenesis of PCOS. In this study, we investigated the effect of miR-145 on cell proliferation and the underlying mechanism of miR-145 in isolated human GCs from the aspirated follicular fluid in women with PCOS. Our findings showed that miR-145 is downregulated in human GCs from PCOS. The miR-145 mimics suppress cell proliferation and promoted cell apoptosis in human GCs from PCOS. However, miR-145 inhibitor promotes cell proliferation and inhibited cell apoptosis. Moreover, using a dual-luciferase reporter assay, we confirmed that the insulin receptor substrate 1 (IRS1) gene is a direct target of miR-145. The miR-145 mimics inhibited messenger RNA and protein IRS1 expression levels, and silencing of IRS1 by small interfering RNA inhibits human GC proliferation, but IRS1 overexpression abrogates the suppressive effect of miR-145 mimics. Furthermore, miR-145 mimics can inhibit the activation of p38 mitogen-activated protein kinase (p38 MAPK) and extracellular signal-regulated kinase (ERK). The IRS1 overexpression abrogates the suppressive effect of miR-145 mimics on MAPK/ERK signaling pathways. Together, miR-145 mimics suppress cell proliferation by targeting and inhibiting IRS1 expression to inhibit MAPK/ERK signaling pathways. Our study further found that high concentrations of insulin decreases the miR-145 expression, upregulates IRS1, and promotes cell proliferation. These observations showed that miR-145 is a novel and promising molecular target for improving the dysfunction of GCs in PCOS.
authors: 1 Department of Obstetrics and Gynecology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China.
authors: Guoqing
authors: G
authors: Cai
authors: 1 Department of Obstetrics and Gynecology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China.
authors: Xiangdong
authors: X
authors: Ma
authors: 1 Department of Obstetrics and Gynecology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China.
authors: Biliang
authors: B
authors: Chen
authors: 1 Department of Obstetrics and Gynecology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China.
authors: Yanhong
authors: Y
authors: Huang
authors: 1 Department of Obstetrics and Gynecology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China.
authors: Shujuan
authors: S
authors: Liu
authors: 1 Department of Obstetrics and Gynecology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China.
authors: Hong
authors: H
authors: Yang
authors: 1 Department of Obstetrics and Gynecology, Xijing Hospital, the Fourth Military Medical University, Xi'an, China.
authors: Wei
authors: W
authors: Zou
mesh_terms: D000328:Adult; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D005260:Female; D020868:Gene Silencing; D006107:Granulosa Cells / Q000187:drug effects / Q000378:metabolism*; D006801:Humans; D007328:Insulin / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism*; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D011085:Polycystic Ovary Syndrome / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C526292:IRS1 protein, human; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; C541010:MIRN145 microRNA, human; D035683:MicroRNAs; D048051:p38 Mitogen-Activated Protein Kinases
keywords: cell proliferation; granulosa cell; miR-145; polycystic ovary syndrome