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Review
. 2024 Jan 11;25(2):903.
doi: 10.3390/ijms25020903.

The Role of MicroRNA, Long Non-Coding RNA and Circular RNA in the Pathogenesis of Polycystic Ovary Syndrome: A Literature Review

Affiliations
Review

The Role of MicroRNA, Long Non-Coding RNA and Circular RNA in the Pathogenesis of Polycystic Ovary Syndrome: A Literature Review

Jenan Sh Nasser et al. Int J Mol Sci. .

Abstract

Polycystic ovary syndrome (PCOS) is the most common endocrine-metabolic disease in females of reproductive age, affecting 4-20% of pre-menopausal women worldwide. MicroRNAs (miRNAs) are endogenous, single-stranded, non-coding, regulatory ribonucleic acid molecules found in eukaryotic cells. Abnormal miRNA expression has been associated with several diseases and could possibly explain their underlying pathophysiology. MiRNAs have been extensively studied for their potential diagnostic, prognostic, and therapeutic uses in many diseases, such as type 2 diabetes, obesity, cardiovascular disease, PCOS, and endometriosis. In women with PCOS, miRNAs were found to be abnormally expressed in theca cells, follicular fluid, granulosa cells, peripheral blood leukocytes, serum, and adipose tissue when compared to those without PCOS, making miRNAs a useful potential biomarker for the disease. Key pathways involved in PCOS, such as folliculogenesis, steroidogenesis, and cellular adhesion, are regulated by miRNA. This also highlights their importance as potential prognostic markers. In addition, recent evidence suggests a role for miRNAs in regulating the circadian rhythm (CR). CR is crucial for regulating reproduction through the various functions of the hypothalamic-pituitary-gonadal (HPG) axis and the ovaries. A disordered CR affects reproductive outcomes by inducing insulin resistance, oxidative stress, and systemic inflammation. Moreover, miRNAs were demonstrated to interact with lncRNA and circRNAs, which are thought to play a role in the pathogenesis of PCOS. This review discusses what is currently understood about miRNAs in PCOS, the cellular pathways involved, and their potential role as biomarkers and therapeutic targets.

Keywords: biomarkers; cardiovascular disease; circadian rhythm; circular RNA (circRNA); infertility; insulin resistance; long coding RNA (lncRNA); microRNA (miRNAs); polycystic ovary syndrome (PCOS); therapeutic targets.

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Conflict of interest statement

None of the authors have any conflict of interest to declare.

Figures

Figure 1
Figure 1
A simplified model showcasing the role of important miRNAs in the pathogenesis of PCOS complications. Upregulated miRNAs are shown in green font, and downregulated miRNAs are shown in red font. The main drivers of PCOS complications are insulin resistance, hyperandrogenism, and other hormonal imbalances. Infertility in PCOS is mediated by insulin resistance, hyperandrogenism, and hormonal imbalance, while CVD risk is affected by hyperandrogenism, insulin resistance, and reduced vascular endothelial health. The figure shows that the inhibition of the PI3K/AKT pathway in cells (due to the up regulation of miR-133a-3p), GLUT4 receptors (due to upregulation of miR-93), and increased expression of IRS-2 proteins (due to downregulation of miR-92a and -92b) play a role in insulin resistance in PCOS. Meanwhile, the downregulation of miR-323-3p, which reduces the activity of IGF-1, and upregulation of miR-93 and -21 in granulosa cells results in hyperandrogenism. Likewise, the downregulation of miR-92a and -92b in theca cells leads to hyperandrogenism by increasing the expression of CYP17 and GATA6 genes which stimulate androgen synthesis. Moreover, dysregulated levels of progesterone, estradiol, and testosterone are affected by the upregulation of miR-18b, -146a, and -135a in follicular fluid, resulting in hormonal imbalance. The downregulation of miR-320a also leads to hormonal variations by reducing the expression of the RUX2 gene, which modulates steroidogenesis in granulosa cells. Additionally, miRNA-339-5p leads to vascular endothelial cell damage by inhibiting SIRT1/PGC-1α and PI3K/AKT signaling pathways, which inhibits EPC migration, tubular formation, and proliferation and contributes to the risk of CVD in PCOS. Created with BioRender.com.
Figure 2
Figure 2
A schematic to illustrate the key genes and proteins involved in the circadian clock interacting with different miRNAs. BMAL1 and CLOCK complex bind to E-box promoter elements, activating the transcription of Per and Cry genes. With a higher accumulation of genes in the cytoplasm, CLOCK:BMAL1 activity is inhibited and prevents gene expression from acting as a negative feedback loop inhibitor [64]. Created with BioRender.com.

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This research received no external funding.