Altered expression of miRNAs in the uterus from a letrozole-induced rat PCOS model

Li, Chunjin; Lu, Ciyong; Zhao, Yun; Chen, Shuxiong; Fu, Li; Jiang, Yanwen; Gao, Shan; Liu, Zhuo; Wang, Fengge; Zhu, Xiaonian; Rao, Jiahui; Zhang, Jing; Zhou, Xu

doi:10.1016/j.gene.2016.10.033

Cited by 36 publications

(25 citation statements)

References 25 publications

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“…Several signal transduction pathways are reported to be involved in insulin resistance, such as peroxisome proliferatoractivated receptors (PPARs) [29][30][31], PI3K, PKC [32], NFκB, and Ras/mitogen-activated protein kinase (MAPK) [33]. Meanwhile, PCOS might be regulated through genetic alterations that activate several signaling pathways, such as the MAPK, PI3K, AKT, ERK1/2, and RAS pathways [29][30][31][34][35][36]. RAP2A belongs to the Ras superfamily, and RAP2A with constitutive activity has been shown to inhibit AKT phosphorylation in B cell lines by binding to PI3K [37].…”

Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: MiR-140 targets RAP2A to enable the proliferation of insulin-treated ovarian granulosa cells

Xiong

Wang

et al. 2020

J Ovarian Res

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Background: We elucidated the role of specific MicroRNAs (miRNAs) in the development of polycystic ovary syndrome (PCOS) and explained the changes in the proliferation of granulosa cells. Excised ovarian cortex specimens were collected for miRNA profiling analysis (n = 20 PCOS females and 5 non-PCOS females). Insulintreated ovarian granulosa cells isolated from mice were used for mechanical studies. Results: High miR-140 expression was observed in PCOS samples and insulin-treated granulosa cells compared to that in non-PCOS and unstimulated cells, respectively. However, the Ras-related protein Rap-2a precursor (RAP2A) was downregulated in in PCOS. MTT assay and EdU staining showed that an miR-140 inhibitor attenuated viability in insulin-treated granulosa cells; cell viability increased with miR-140 overexpression. Reduced expression of miR-140 and the expression of the miR-140 mimic resulted in marked cell apoptosis, as evidenced by the results of PI flow cytometry and Annexin V-FITC; miR-140 overexpression results in downregulated RAP2A expression, and the miR-140 mimic directly bound to the RAP2A 3′-UTR, causing increase in RAP2A levels in insulin-treated granulosa cells; RNA-mediated silencing of RAP2A in insulin-treated granulosa cells restored cell proliferation and apoptosis to normal levels. Phosphorylated AKT was found to be negatively regulated through cross-talk between miR-140 and RAP2A. Conclusions: In conclusion, PCOS ovarian cortex specimens and insulin-treated granulosa cells showed elevated expression of miR-140, which could lead to increased proliferation and reduced apoptosis of cells by targeting RAP2A. This study may pave the way for future research on the properties of granulosa cells in PCOS.

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Section: Discussionmentioning

confidence: 99%

RETRACTED ARTICLE: MiR-140 targets RAP2A to enable the proliferation of insulin-treated ovarian granulosa cells

Xiong

Wang

et al. 2020

J Ovarian Res

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“…Through the bioinformatics analysis, we found that there were certain miRNAs that seemed to play important roles in Heqi San-induced therapeutic effect on the PCOS model. Previous work has demonstrated that expression of miRNAs in the uterus of a rat PCOS model was significantly altered [ 44 ]. This is consistent with the general concept that the abnormal expression of miRNAs is correlated with various disorders [ 45 ].…”

Section: Discussionmentioning

confidence: 99%

Beneficial effects of Heqi san on rat model of polycystic ovary syndrome through the PI3K/AKT pathway

et al. 2017

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BackgroundHeqi San, a traditional Chinese medicine (TCM) has been reported to regulate hormone levels in patients with metabolic disease, suggesting a potential clinical application. In the current study, we aimed to elucidate the effect of Heqi San on rat model of polycystic ovary syndrome (PCOS).MethodPCOS model was established in female SD rats. Rats were randomly divided into four groups: the control, untreated PCOS model, Heqi San treated PCOS model (8.1 g/kg) and metformin (MET) treated PCOS model (135 mg/kg) groups. All animals were subcutaneously injected with 6 mg/100 g dehydroepiandrosterone (DHEA) in the neck once a day for 20 consecutive days. The serum hormone levels were measured by ELISA. The ovarian tissues were stained with hematoxylin and eosin (HE) to undergo pathological examination. The expression levels of GLTU4 and PTEN mRNA were examined by real time PCR. The crucial proteins in the PI3K/APT pathway were analyzed by western blotting. Then, the functions of the target genes were analyzed using bioinformatics approaches.ResultsWe found that Heqi San was able to recover the serum hormone levels and improve insulin resistance in PCOS rat model. A morphological lesion of the ovary was also restored with the Heqi San treatment. More importantly, we discovered a correlation between the PI3K/AKT signaling pathway and the beneficial effects of Heqi San, demonstrating that its application could alter the expression levels of p-ERK, p-AKT, p-GSK3β, IRS-1, PTEN and GLTU4, all key factors in the PI3K/APT pathway. Through a bioinformatical analysis, we predicted the related gene function and pathway of the pathological mechanism of PCOS and found miRNAs that are likely to be critical in PCOS occurrence, including rno-miR-144-3p, rno-miR-30c-2-3p, rno-miR-486, rno-miR-3586-3p and rno-miR-146b-5p.ConclusionThe beneficial effects of Heqi on PCOS, including alter serum hormone levels, recover ovary morphological lesions and improve insulin resistance, which is mediated through the PI3K/AKT pathway.Graphical abstractThe potential role of miRNA-144-3p in PCOS pathogenesis.

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“…miRNAs consist of a group of small non-coding RNAs, some of which play key roles in modulating the functions of human bodies (25,34,35). Numerous miRNAs have been demonstrated to be involved in endocrine and metabolic diseases (36,37), and several miRNAs (e.g., miR-93 and miR-145) have been reported to be involved in the pathogenesis of PCOS (27)(28)(29)(30)(31)(38)(39)(40)(41)(42). miRNA-93 was initially revealed to play an important role in modulating GLUT4 expression, and thus be involved in the development of insulin resistance in PCOS patients (27).…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-33b-5p is overexpressed and inhibits GLUT4 by targeting HMGA2 in polycystic ovarian syndrome: An in vivo and in vitro study

Yang

Jiang

Xiao³

et al. 2018

Oncol Rep

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Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disease, but its pathogenesis remains largely unknown. The present study explored the role of microRNA‑33b‑5p (miR‑33b‑5p) in PCOS pathogenesis, with a particular focus on its role in regulating glucose transporter 4 (GLUT4). A rat model of PCOS was developed by injecting female SD rats with insulin and HCG. miR‑33b‑5p, GLUT4, sterol regulatory element‑binding protein 1 (SREBF1), and high mobility group A2 (HMGA2) expression in rat ovarian tissues was examined by qRT‑PCR and immunohistochemistry. The effect of a high dose of either glucose or insulin on miR‑33b‑5p, GLUT4, SREBF1 and HMGA2 expression was also examined in cultured adipocytes by qRT‑PCR and western blotting. Additionally, the luciferase reporter assay and chromatin immunoprecipitation (ChIP) were used to explore the role of miR‑33b‑5p in regulating HMGA2, SREBF‑1 and/or GLUT4. Elevated levels of miR‑33b‑5p expression were detected in the ovarian tissues of insulin resistant PCOS rats, and those levels were negatively correlated with those of GLUT4, HMGA2 and SREBF1 expression (P<0.05). Immunohistochemistry studies revealed that GLUT4, SREBF1, and HMGA2 expression levels in the ovarian tissues of insulin resistant PCOS rats were significantly lower than those in other groups of rats. In cultured adipocytes, excess extracellular glucose or insulin increased miR‑33b‑5p expression but reduced GLUT4, SREBF1 and HMGA2 expression, whereas the levels of GLUT4, SREBF1 and HMGA2 were elevated by inhibition of miR‑33b‑5. HMGA2 could directly bind to the 5'‑promoter region of GLUT4 and promote its expression, and could also promote SREBF1 expression. Moreover, SREBF1 could also directly bind to the 5'‑promoter region of GLUT4 and promote its expression. Our findings revealed that miR‑33b‑5p was overexpressed in the ovarian tissues of insulin resistant PCOS rats, and thus may play an important role in the development of insulin resistance in PCOS patients. miR‑33b‑5p can inhibit GLUT4 production by targeting HMGA2, and in addition, HMGA2 and SREBF1 are important molecules involved in modulating GLUT4 expression.

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Altered expression of miRNAs in the uterus from a letrozole-induced rat PCOS model

Cited by 36 publications

References 25 publications

RETRACTED ARTICLE: MiR-140 targets RAP2A to enable the proliferation of insulin-treated ovarian granulosa cells

RETRACTED ARTICLE: MiR-140 targets RAP2A to enable the proliferation of insulin-treated ovarian granulosa cells

Beneficial effects of Heqi san on rat model of polycystic ovary syndrome through the PI3K/AKT pathway

MicroRNA-33b-5p is overexpressed and inhibits GLUT4 by targeting HMGA2 in polycystic ovarian syndrome: An in vivo and in vitro study

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