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Role of peroxiredoxin2 downregulation in recurrent miscarriage through regulation of trophoblast proliferation and apoptosis.

ABSTRACT: Peroxiredoxin (Prdx) 2 is an antioxidant protein that utilizes its redox-sensitive cysteine groups to reduce hydrogen peroxide molecules and protect cells against oxidative damage from reactive oxygen species (ROS). However, its function in trophoblasts at the maternal-fetal interface has not been clarified yet. In this study, significantly lower Prdx2 expression was found in the first-trimester villous cytotrophoblasts of patients with recurrent miscarriage (RM) than in cytotrophoblasts from healthy controls. Further, Prdx2 knockdown inhibited proliferation and increased apoptosis of trophoblast cells. The reason for this may be an increase in the level of cellular ROS after knockdown of Prdx2, which may subsequently lead to an increase in the expression of phosphorylated p53 (p-p53) and p38-MAPK/p21. Prdx2 knockdown also impaired the fusion of BeWo cells induced by forskolin. Bioinformatics analysis identified a c-Myc-binding site in the Prdx2 promoter region, and chromatin immunoprecipitation verified that c-Myc directly bound to a site in this locus. Suppression and overexpression of c-Myc resulted in reduction and increase of Prdx2 expression respectively. Furthermore, we demonstrated that c-Myc was downregulated in the first-trimester cytotrophoblasts of patients with RM, and its downregulation is also related with inhibited cell proliferation, increased apoptosis, as well as upregulated p21 expression and p-p53/p53 ratio. Our findings indicate that Prdx2 might have an important role in the regulation of trophoblast proliferation and apoptosis during early pregnancy, and that its expression is mediated by c-Myc. Thus, these two proteins may be involved in the pathogenesis of RM and may represent potential therapeutic targets.

SUBMITTER: Wu F

PROVIDER: S-EPMC5520946 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:AimRecurrent miscarriage (RM) is associated with numerous clinical factors. However, some RM occurred without specific factors. It has been revealed that some molecules such as hormones, miRNAs, and transcription factors are involved in RM by regulating proliferation, apoptosis, etc. However, the mechanism of RM has yet to be identified clearly. Circular RNAs (circRNAs) are a class of endogenous non-coding RNAs that often act as sponges for miRNAs or binds to proteins involved in biological processes. However, the functional role of circRNAs in the uterine decidua of patients with early RM is still unclear. In this study, we aimed to investigate the mechanisms of circ-CYP24A1 in RM.MethodsThe Dual-Luciferase Activity Assay was designed to analyze the bonding between circ-CYP24A1 and miR-224, and miR-224 and prolactin receptor (PRLR) mRNA 3'UTR. In situ hybridization (ISH) and immunohistochemistry (IHC) were used to observe the expression of circ-CYP24A1 and PRLR in the decidua. Rescue experiments were performed to investigate the regulating effects of circ-CYP24A1, miR-224, and PRLR. Western blotting was conducted to test the expression level of PRLR. The proliferation and apoptosis-related markers in Ishikawa cells were analyzed using CCK8, immunofluorescence staining, and the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay.ResultsIn this study, based on the microarray analysis data, we identified a high level of circ-CYP24A1 and PRLR in the decidua of patients with early RM. Based on the bioinformatics prediction, the binding relationship between circ-CYP24A1 and miR-224, as well as miR-224 and PRLR, were verified. Functional experiments demonstrated that circ-CYP24A1 regulated proliferation and apoptosis by binding to and inhibiting miR-224, resulting in increased PRLR expression. Taken together, this study provides new insights into the mechanism of RM.ConclusionIn this study, we found that circ-CYP24A1 plays a role in RM by impairing the balance of cell proliferation and apoptosis by sponging miR-224, thereby regulating PRLR.

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Role of peroxiredoxin2 downregulation in recurrent miscarriage through regulation of trophoblast proliferation and apoptosis.

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