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MiR-140 targets RAP2A to enable the proliferation of insulin-treated ovarian granulosa cells
Zhengfang Xiong1, Bing Li2, Wenjuan Wang1
1Reproductive Medical Center, Qinghai Provincial People's Hospital, No. 2, Gonghe Road, Xining, 810007, Qinghai, China.
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). Insulin-treated 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.
Insights
Polycystic ovary syndrome (PCOS) involves elevated miR-140, a microRNA that increases granulosa cell proliferation and reduces apoptosis by targeting RAP2A. This finding offers new insights into PCOS pathogenesis.
Area of Science:
- Endocrinology
- Molecular Biology
- Reproductive Biology
Background:
- Polycystic ovary syndrome (PCOS) is a complex endocrine disorder.
- Granulosa cell proliferation is altered in PCOS.
- Specific microRNAs (miRNAs) are implicated in PCOS development.
Purpose of the Study:
- To elucidate the role of specific miRNAs in PCOS development.
- To investigate changes in granulosa cell proliferation in PCOS.
- To identify the molecular mechanisms underlying these changes.
Main Methods:
- miRNA profiling of ovarian cortex specimens from PCOS and non-PCOS females.
- Mechanical studies using insulin-treated mouse granulosa cells.
- MTT assay, EdU staining, PI flow cytometry, and Annexin V-FITC for cell viability and apoptosis analysis.
Main Results:
- miR-140 expression was significantly higher in PCOS samples and insulin-treated granulosa cells.
- miR-140 inhibition attenuated granulosa cell viability, while overexpression increased it.
- miR-140 targeted RAP2A, affecting granulosa cell proliferation and apoptosis via AKT signaling.
Conclusions:
- Elevated miR-140 in PCOS contributes to increased granulosa cell proliferation and reduced apoptosis by targeting RAP2A.
- This study provides a molecular basis for understanding granulosa cell dysfunction in PCOS.
- Findings suggest potential therapeutic targets for PCOS management.
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