Expression Of MicroRNA-183/96/182 Cluster In Polycystic Ovary Syndrome With Insulin Resistance And The Clinical Significance

Context:Insulin resistance(IR)of granulosa cells may account for the ovarian dysfunctions observed in polycystic ovarian syndrome(PCOS).The underlying mechanism remains largely unresolved.MicroRNAs(microRNA,miRNA)are a class of non-coding RNA at the length of 21-24 nuclear acid,that regulate gene expression post-transcriptionally through cleavage or translational regression of specific target messenger RNAs(mRNAs).The miR-183/96/182 cluster regulates multiple genes in insulin signaling and lipid or energy metabolism pathways,also controlling steroidogenesis,proliferation and apoptosis in granulosa cells.Objective:To explore the relationship of IR of granulosa cells with the expression of miR-183/96/182 cluster in granulosa cells in PCOS,and to assess the clinical significance.Methods:72 healthy female volunteers with regular menstruation and 120 women with PCOS(divided into IR and NIR subgroups),aged 20-35 years,were prospectively assessed.Main outcome measures were miRNA amounts assessed by qPCR,comparison between groups,and associations with clinical features.The area under the receiver operating characteristic(ROC)curve(AUC)was calculated to evaluate the predictive power of miRs for PCOS insulin resistance.Results:In PCOS groups,some of the measurements such as blood pressure,LH,LH/FSH,T,AMH,FPG,FINS,HOMA-IR,LDLC,TG,ALT,AST,GGT in all PCOS groups were higher than in controls,whereas FSH,HDLC and AST/ALT were lower in the PCOS groups as compared to the controls.Relative expression levels of the miR-183/96/182 cluster were significantly higher in granulosa cells from PCOS compared with those from controls(fold-change:7.41,3.73,4.57,p<0.05).miR-183 and miR-182 showed significantly higher levels in PCOS-IR subjects than PCOS-NIR patients(fold-change:3.98,3.97,p<0.05).BMI were matched and the expression levels compared;the results were similar to BMI-unmatched data.Meanwhile,miR-183 were positively associated with fasting insulin(FINS)(r=0.7783,p=0.0017),homeostasis model assessment-insulin resistance(HOMA-IR)(r=0.6341,p=0.0199),alanine transaminase/aspartate transaminase(AST/ALT)(r=0.720,p=0.004),and alkaline phosphatase(ALP)(r=0.603,p=0.023).miR-182 were positively associated with FINS(r=0.7639,p=0.003),HOMA-IR(r=0.7590,p=0.0042),AST/ALT(r=0.6454,p=0.0234).Furthermore,bioinformatics analysis indicated that genes targeted by miR-183 and miR-182 were involved in PI3K-AKT signaling,insulin signaling,the cell cycle and oocyte meiosis.MiR-183 yielded an area under the receiver operating characteristic(ROC)curve of 0.748(95%confidence interval[CI]0.661-0.835)in discriminating PCOS with IR from controls;miR-182 yielded 0.738(95%CI 0.651-0.825).miR-183 displayed sensitivity and specificity of 70.1%and 74.6%,respectively,at a cut-off value of 1.725 in discriminating PCOS with IR from healthy controls;miR-182 had 66.7%and 74.6%,respectively,at a cut-off value of 1.614.Conclusion:The miR-183/96/182 cluster is highly expressed in PCOS;in addition,miR-183 and miR-182 are associated with insulin resistance,and could serve as biomarkers of IR in PCOS.