Elevated levels of miR-483-5p in oocytes aggravates premature ovarian insufficiency induced by CDDP by targeting the FKBP4

Abstract

Background: Premature ovarian insufficiency (POI) is characterized by a loss of ovarian function before 40 years-of-age and represents an existing challenge cause of female infertility. POI is one of the dominant causes of cis-diaminedichloroplatinum (cisplatin, CDDP)-induced reproductive impairment. However, the detailed mechanisms underlying POI induced by CDDP remain unclear.Methods: The POI C57B6/J mouse model was created by administering CDDP. The effects of FKBP4 were investigated using isobaric tags for relative and absolute quantification analysis (iTRAQ), real-time quantitative PCR (qRT-PCR) and western blotting. Target prediction was predicted using TargetScan software. Levels of sex hormones were tested using Enzyme-linked immunosorbent assays (ELISA).Results: We found that the FKBP4 protein was down-regulated in the ovaries of CDDP model. Target prediction identified FKBP4 as a potential target for miR-483-5p, which was expressed at high levels in both the ovaries and serum of CDDP-POI mice, and in the serum from POI patients. In vitro experiments further confirmed that FKBP4 was the target for miR-483-5p in human cervical cancer cells (HeLa). The overexpression of FKBP4 in human granulosa cells (KGN) alleviated the apoptosis caused by CDDP and the overexpression of miR-483-5p. Furthermore, the overexpression of miR-483-5p in oocytes caused injury to the ovaries, and disrupted the levels of sex hormones in CDDP-POI mice (AMH: P < 0.01; E2: P < 0.01; FSH: P < 0.01).Conclusions: Analyses showed that miR-483-5p targets the FKBP4 protein in a mouse model of POI induced by CDDP. Elevated levels of miR-483-5p in oocytes could aggravate POI induced by CDDP by targeting FKBP4. Overall, our data demonstrate that miR-483-5p was responsible for the underlying pathophysiology of POI induced by chemotherapeutic treatments, such as CDDP.

The Role of Noncoding RNA in the Pathophysiology and Treatment of Premature Ovarian Insufficiency

“…They found that FKBP4 ovarian expression was significantly decreased in POI and confirmed that this protein is a target of miR-483-5p. Upregulation of miR-483-5p increases ovarian sensitivity to cisplatin and causes severe ovarian dysfunction [76]. Additionally, high-fat and high-sugar diet supplementation was revealed to activate the Dab2ip/Ask1/p38-Mapk signaling pathway and to promote gamma H2A histone family member X (γH2AX) phosphorylation by inhibiting the expression of endogenous miR-146b-5p, which results in granulosa cell ageing and POI development [77].…”

“…This very recent study identified a new lncRNA-ALDOA complex through which ZNF674-AS1 exerts its functions, in line with a previous study contributing to our understanding of epigenetic regulation of granulosa cell function [83]. miR-449b miR-320 E2F1 [63,64] miR-133b FOXl2 [65] miR-132 StAR, 3βHSD, 20αHSD [65] miR-23a XIAP [66] miR-23a miR-27a SMAD5 [67] miR-379-5p PARP1 XRCC6 [68] miR-127-5p HMGB2 [69] miR-21 Peli1 [70] miR-29a miR-144 PLA2G4A [72] miR-15b αKlotho mRNA TGFβ/SMAD pathway [74] miR-483-5p FKBP4 [76] miR-146b-5p Dab2ip/Ask1/p38-MAPK γH2AX [77] miR-125a-5p STAT3 [75] TNFSF10 = tumor necrosis factor superfamily member 10; FNDC1 = fibronectin type III domain containing 1; ESR1 = estrogen receptor 1; PTEN = phosphatases and tensin homolog; IRAK1 = interleukin-1 receptor-associated kinase; TRAF6 = tumor necrosis factor receptor-associated factor 6; FOXO3 = forkhead box O; CCND2 = cyclin D2; E2F1 = estrogen receptor-associated transcription factor; FOXl2 = forkhead box L2; StAR = steroidogenic acute regulatory protein; 3βHSD = 3β-hydroxysteroid dehydrogenase; 20αHSD = 20α-hydroxysteroid dehydrogenase; XIAP = X-linked inhibitor of apoptosis protein; SMAD5 = others against decapentaplegic homolog 5; PARP1 = poly (ADP-ribose) polymerase 1; XRCC6 = X-ray repair cross-complementing 6; HMGB2 = highmobility group box 2; Peli1 = Pellino-1; PLAG24A = phospholipase A2 group IVA; TGFβ = transforming growth factor β; FKBP4 = FK506-binding protein 4; γH2AX = gamma H2A histone family member X; Dab2ip = DAB2 interacting protein; Ask1 = apoptosis signal-regulating kinase 1; p38-MAPK = p38 mitogen-activated protein kinase; STAT3 = signal transducer and activator of transcription 3.…”