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Long non-coding RNA lnc-CCNL1-3:1 promotes granulosa cell apoptosis and suppresses glucose uptake in women with polycystic ovary syndrome.

ABSTRACT: Polycystic ovary syndrome (PCOS) is a common endocrine and metabolic disease in premenopausal women. Long non-coding RNAs (lncRNAs) constitute important factors in numerous biological processes. However, their roles in PCOS pathogenesis require further clarification. Our study aims to elucidate the roles of lncRNA lnc-CCNL1-3:1 (CCNL) in PCOS. CCNL expression in human luteinized granulosa cells (hLGCs) derived from women with and without PCOS was detected. The full length of CCNL was obtained by 5' and 3' rapid amplification of cDNA ends. CCNL roles in granulosa cell apoptosis, mitochondrial function, and glucose uptake were evaluated. The binding relationship between CCNL and forkhead box O1 (FOXO1) was determined by RPISeq, RNA immunoprecipitation, subcellular fractionation, and immunofluorescence. In KGN cells and hLGCs, CCNL overexpression upregulated FOXO1 expression, promoted cell apoptosis, reduced glucose transport capability, and impaired mitochondrial function, and these effects were partially abolished by silencing FOXO1. The interaction of CCNL with FOXO1 might prevents FOXO1 exclusion from the nucleus and subsequent degradation in the cytosol. We determined that CCNL serve as a facilitator in the processes of PCOS. CCNL might participate in PCOS pathologies such as follicular atresia and insulin resistance.

SUBMITTER: Huang J

PROVIDER: S-EPMC7819816 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Whole Genome Transcriptomic Analysis of Ovary Granulosa Cells Revealed an Anti-Apoptosis Regulatory Gene DLGAP5 in Polycystic Ovary Syndrome.

Project description:The mechanisms underlining pathogenesis of polycystic ovary syndrome (PCOS) remain largely unknown. Dysfunction of ovarian granulosa cells plays an important role. The present study performed the lncRNA and mRNA profiling by whole genome transcriptomic sequencing of ovary granulosa cells from women with PCOS and investigated the potential role of differentially expressed gens (DEGs) in the pathomechanism of PCOS. In total, 1,936 DEGs (30 upregulated and 1,906 downregulated mRNAs and lncRNAs) were identified in the ovary granulosa cells between control and PCOS group. Functional enrichment analysis showed that DEGs were mainly associated with cytokine-cytokine receptor interaction, neuroactive ligand-receptor interaction, and olfactory transduction. qRT-PCR validated the upregulation of DLGAP5 mRNA in ovary from PCOS group when compared to control group. Immunostaining and TUNEL assays showed that DLGAP5 protein level was increased while apoptosis was decreased in follicles of ovary in PCOS group. In vitro functional assays showed that DLGPA5 knockdown repressed viability and proliferation, but enhanced apoptosis and disrupted cell cycle in granulosa cells; while DLGAP5 overexpression had the opposite effects in granulosa cells. In conclusion, the study showed differentially expressed lncRNA and mRNA profile in the granulosa cells in ovaries of PCOS. Functional results demonstrated that DLGAP5 is a dysregulated candidate gene in the pathogenesis of PCOS, especially granulosa cell apoptosis and proliferation.

| S-EPMC8971550 | biostudies-literature

Coding and Non-coding gene expression signatures of granulosa cells from Polycystic Ovary Syndrome Patients

Project description:Polycystic ovary syndrome (PCOS), one of the most common endocrinal diseases among reproductive-aged women,is characterized by hyperandrogenemia, chronic oligo/anovulation and polycystic ovarian morphology. In this research, we presented microarrays to identify the differential expressed protein-coding genes and lncRNAs expression profile in the luteinized granulosa cells obtained from PCOS and healthy control patients.

2018-10-30 | GSE114419 | GEO

Comprehensive analysis of genome-wide DNA methylation across human polycystic ovary syndrome ovary granulosa cell.

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MiRNA-99a can regulate proliferation and apoptosis of human granulosa cells via targeting IGF-1R in polycystic ovary syndrome.

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| S-EPMC6420594 | biostudies-literature

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| S-EPMC8374745 | biostudies-literature

MiR-93-5p promotes granulosa cell apoptosis and ferroptosis by the NF-kB signaling pathway in polycystic ovary syndrome.

Project description:Polycystic ovary syndrome (PCOS) is one of the most common endocrine disorders in women of reproductive age. miR-93-5p has been reported to be elevated in granulosa cells of PCOS patients. However, the mechanism by which miR-93-5p drives granulosa cell (GC) progression remains unclear. Thus, this study focuses on the roles and mechanisms of miR-93-5p in the GCs of PCOS.MethodsKGN cells have similar ovarian physiological characteristics and are used to study the function and regulatory mechanism of GCs. In this study, KGN cells were transfected with si-NC, si-miR93-5p, oe-NC and oe-miR93-5p. A cell counting kit-8 assay, flow cytometry and western blotting were performed to observe the proliferation and apoptosis of KGN in different groups. Subsequently, the levels of reactive oxygen species, malondialdehyde, GPX4, SLC7A11 and Nrf2, which are indicators of ferroptosis, were measured by a dihydroethidium fluorescent dye probe, biochemical kit, western blotting and reverse transcription quantitative polymerase chain reaction. Ultimately, bioinformatic analysis and experimental methods were used to examine the interaction between miR-93-5p and the NF-κB signaling pathway.ResultsmiR-93-5p was upregulated in the GCs of PCOS patients. Overexpression of miR-93-5p promoted apoptosis and ferroptosis in KGN cells, while knockdown of miR-93-5p showed the reverse effect. Biological analysis and subsequent experiments demonstrated that miR-93-5p negatively regulates the NF- κB signaling pathway.ConclusionmiR-93-5p promotes the apoptosis and ferroptosis in GC by regulating the NF-κB signaling pathway. Silencing of miR-93-5p protects against GC dysfunction. Our study identified miR-93-5p as a new molecular target for improving the function of GCs in PCOS patients.

| S-EPMC9626535 | biostudies-literature

MicroRNA-664a-3p inhibits the proliferation of ovarian granulosa cells in polycystic ovary syndrome and promotes apoptosis by targeting BCL2A1.

Project description:BackgroundTo investigate whether micro ribonucleic acid-664a-3p (miR-664a-3p) targeting BCL2A1 affects the proliferation and apoptosis of ovarian granulosa cells.MethodsReal-time quantitative polymerase chain reaction (qRT-PCR) was used to detect the expression of miR-664a-3p in granulosa cells, granular tumor cell lines (KGN), and normal ovarian epithelial cell lines (IOSE80) in the polycystic ovary syndrome (PCOS) group and the control group. After overexpressing miR-664a-3p or inhibiting its expression in KGN cells, qRT-PCR and Western blotting were used to detect the messenger RNA (mRNA) and protein levels of related genes. At the same time, a cell counting kit-8 (CCK-8) and flow cytometer were used to detect cell proliferation and apoptosis. The TargetScan website was used to predict the potential binding sites of miR-664a-3p and B-cell lymphoma 2-related protein A1 (BCL2A1), which was further verified by qRT-PCR, Western blotting, and the luciferase reporter gene method.ResultsThe expression of miR-664a-3p was significantly decreased in both PCOS tissues and KGN cells (both P<0.05), and the overexpression of miR-664a-3p inhibited the proliferation of KGN cells and induced their apoptosis. Moreover, our results confirmed that miR-664a-3p directly targets BCL2A1 (P<0.05), and the inhibitory effect of miR-664a-3p on KGN cells was reversed by BCL2A1 overexpression (both P<0.05). The up-regulation of BCL2A1 promotes cell proliferation and reduces cell apoptosis by the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway (both P<0.05).ConclusionsThe up-regulation of miR-664a-3p inhibits the proliferation of KGN cells and increases apoptosis by down-regulating the expression of BCL2A1 and blocking the MAPK/ERK signaling pathway.

| S-EPMC8184414 | biostudies-literature

Plumbagin inhibits proliferation and promotes apoptosis of ovarian granulosa cells in polycystic ovary syndrome by inactivating PI3K/Akt/mTOR pathway.

Project description:Polycystic ovary syndrome (PCOS) is recognized as a general endocrine disease and reproductive disorder. Although evidence indicates that PCOS has a complex etiology and genetic basis, the pathogenic mechanisms and signal pathway in PCOS remain unclear. In this study, the normal structure of follicle and corpus luteum were observed, and no cyst nor hyperemia was observed under the light microscopic study with hematoxylin and eosin (H&E) staining. Eestosterone and progesterone were evaluated by radioimmunoassay in rat serum. The alterations of proliferative ability and cell cycle distribution of each group were assessed by Cell Counting Kit-8 (CCK8) assay and flow cytometry. The protein expression of p-mTOR/mTOR, p-PI3K/PI3K, p-AKT/AKT, and GAPDH were analyzed by western blotting. Both doses of PLB could benefit the ovarian morphology and polycystic property. PLBinduced a suppress effect on the proliferation of rat ovarian granulosa cells. In addition, PLB also induced concentration-dependent apoptosis in rat ovarian granulosa cells. The rat ovarian granulosa cells treated with PLB that the expression levels of p-AKT, p-mTOR, and p-PI3K were significantly decreased in a concentration-dependent manner. PLB not only plays a critical role in attenuating the pathology and polycystic property changes in the ovary but can also induce rat ovarian granulosa cell apoptosis through the PI3K/Akt/mTOR signal pathway. This study showed the innovative role of PLB in the pathogenesis of PCOS and provides a new therapeutic modality for the treatment of PCOS.

| S-EPMC7473319 | biostudies-literature

Long non-coding RNA HLA-F antisense RNA 1 inhibits the maturation of microRNA-613 in polycystic ovary syndrome to promote ovarian granulosa cell proliferation and inhibit cell apoptosis.

Project description:MicroRNA-613 (miR-613) inhibits granulosa cell proliferation, suggesting its involvement in polycystic ovary syndrome (PCOS). We predicted that long non-coding RNA (lncRNA) HLA-F antisense RNA 1 (HLA-F-AS1) could interact with premature miR-613. We then explored the crosstalk between HLA-F-AS1 and miR-613 in PCOS. In this study, follicular fluid donated by 58 healthy controls and 58 PCOS patients was used to analyze the expression of HLA-F-AS1 and miR-613 (mature and premature). The direct interaction between HLA-F-AS1 and premature miR-613 was evaluated by RNA pull-down assay. Overexpression of both HLA-F-AS1 and miR-613 was achieved in granulosa cells to assess their interactions. Cell proliferation and apoptosis were detected with BrdU assay and cell apoptosis assay, respectively. We found that miR-613 was highly expressed in PCOS, while HLA-F-AS1 was downregulated in PCOS. HLA-F-AS1 directly interacted with premature miR-613, and overexpression of HLA-F-AS1 increased the expression levels of premature miR-613, but decreased the expression levels of mature miR-613. HLA-F-AS1 increased ovarian granulosa cell proliferation and inhibited cell apoptosis. MiR-613 played an opposite role and suppressed the role of HLA-F-AS1. Therefore, HLA-F-AS1 may inhibit the maturation of miR-613 in PCOS to promote ovarian granulosa cell proliferation and inhibit cell apoptosis.

| S-EPMC9275988 | biostudies-literature

The HMGA2-IMP2 Pathway Promotes Granulosa Cell Proliferation in Polycystic Ovary Syndrome.

Project description:ContextThe high mobility group AT hook 2 (HMGA2) gene was previously identified in a genome-wide association study as a candidate risk gene that might be related to polycystic ovary syndrome (PCOS). Whether HMGA2 contributes to promoting granulosa cell (GC) proliferation in PCOS remains unknown.ObjectiveWe sought to determine whether HMGA2 is involved in the ovarian dysfunction of PCOS and in the mechanism of increased GC proliferation.Patients and cellsmRNA expression was analyzed in ovarian GCs from 96 women with PCOS and 58 healthy controls. Immortalized human GCs (KGN and SVOG cells) were used for the mechanism study.Main outcome measuresmRNA expression in ovarian GCs was measured using quantitative RT-PCR, and KGN cells were cultured for proliferation assays after overexpression or knockdown of target genes. Protein expression analysis, luciferase assays, and RNA binding protein immunoprecipitation assays were used to confirm the mechanism study.ResultsHMGA2 and IGF2 mRNA binding protein 2 (IMP2) were highly expressed in the GCs of women with PCOS, and the HMGA2/IMP2 pathway promoted GC proliferation. Cyclin D2 and SERPINE1 mRNA binding protein 1 were regulated by IMP2 and were highly expressed in women with PCOS.ConclusionsThe HMGA2/IMP2 pathway was activated in women with PCOS and promoted the proliferation of GCs. This might provide new insights into the dysfunction of GCs in PCOS.

| S-EPMC6753588 | biostudies-literature

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