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[miR-483-5p aggravates cisplatin-induced premature ovarian insufficiency in rats by targeting FKBP4]
1Department of Obstetrics and Gynecology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
Objective:
To investigate the role of FKBP4 protein in cisplatin-induced premature ovarian insufficiency (POI).
Objective:
We performed ITRAQ assay of the ovarian tissues from 4 mice with cisplatin-induced POI and 4 control mice, and identified FKBP4 as a significantly down-regulated protein in the oocytes and granulosa cells following cisplatin treatment. TargetScan software was used for target analysis of FKBP4, and qRT-PCR and Western blotting were used to verify the expression levels of miR-483-5p and FKBP4 in the mouse models. Serum samples were collected from patients with POI and healthy women for detecting miR-483-5p level with qRT-PCR. Cell transfection and dual-luciferase assay were performed to determine the relationship between miR-483-5p and FKBP4. In primary granulosa cells and KGN cells, we examined the effect of miR-483-5p alone, miR-483-5p and cisplatin, and miR-483-5p combined with both cisplatin and FKBP4 on cell apoptosis. We also assessed ovarian function in a transgenic mouse model with ovarian miR-483-5p overexpression in comparison wigh wildtype mice using immunofluorescence assay, in situ hybridization and ELISA.
Objective:
Ovarian FKBP4 expression was significantly decreased in mice with cisplatin-induced POI. Analysis using TargetScan software indicated that FKBP4 was the potential target of miR-483-5p, which was highly expressed in the ovaries and serum of POI mice and in the serum of patients with POI. In vitro experiments further confirmed that FKBP4 was the target of miR-483-5p. In KGN and primary granulosa cells, FKBP4 overexpression significantly reduced cell apoptosis induced by both cisplatin and miR-483-5p overexpression (P= 0.0045 and 0.0177, respectively). In the transgenic mice with miR-483-5p overexpression in the oocytes, cisplatin induced more severe ovarian damages as compared with those in the wild-type mice.
Objective:
miR-483-5p/FKBP4 is a new and important pathway in cisplatin-induced POI, in which cisplatin increases ovarian miR- 483-5p expression to result in targeted downregulation of FKBP4. Up-regulation of miR-483-5p may increase ovarian sensitivity to cisplatin and cause severe ovarian dysfunction. Detection of serum miR-483-5p level may help to predict the occurrence and development of POI.
Insights
Cisplatin treatment downregulates FKBP4 protein, a key factor in premature ovarian insufficiency (POI). Elevated miR-483-5p levels contribute to ovarian damage by targeting FKBP4, suggesting its potential as a diagnostic marker for POI.
Area of Science:
- Reproductive Biology
- Molecular Endocrinology
- Oncology
Background:
- Cisplatin is a chemotherapy agent known to cause ovarian toxicity.
- Premature ovarian insufficiency (POI) is a condition characterized by the loss of ovarian function before age 40.
- The molecular mechanisms underlying cisplatin-induced POI are not fully understood.
Purpose of the Study:
- To investigate the role of FKBP4 protein in cisplatin-induced premature ovarian insufficiency (POI).
- To elucidate the regulatory relationship between miR-483-5p and FKBP4 in the context of ovarian damage.
- To assess the potential of miR-483-5p as a biomarker for POI.
Main Methods:
- ITRAQ assay on ovarian tissues from cisplatin-treated and control mice.
- Quantitative real-time PCR (qRT-PCR) and Western blotting to assess gene and protein expression.
- Bioinformatic analysis (TargetScan) to predict microRNA targets.
- Cell transfection, dual-luciferase assays, and apoptosis assays in granulosa cells (KGN and primary).
- Analysis of ovarian function in transgenic mice overexpressing miR-483-5p.
Main Results:
- FKBP4 was significantly downregulated in oocytes and granulosa cells of mice with cisplatin-induced POI.
- FKBP4 was identified as a direct target of miR-483-5p, which was upregulated in POI models and patients.
- Overexpression of FKBP4 attenuated cisplatin- and miR-483-5p-induced apoptosis in granulosa cells.
- Transgenic mice overexpressing miR-483-5p exhibited exacerbated ovarian damage upon cisplatin treatment.
Conclusions:
- The miR-483-5p/FKBP4 pathway plays a critical role in cisplatin-induced POI.
- Cisplatin induces POI by upregulating miR-483-5p, leading to FKBP4 downregulation and increased ovarian sensitivity to damage.
- Serum miR-483-5p levels may serve as a predictive biomarker for the development and progression of POI.
