The Role of miRNA and Related Pathways in Pathophysiology of Uterine Fibroids—From Bench to Bedside

Abstract

Uterine fibroids (UFs) are the most common benign tumors of the female genital tract. Their prevalence usually is estimated at 30–40%, but may reach up to 70–80% in predisposed groups of women. UFs may cause various clinical issues which might constitute the major reason of the overall deterioration of the quality of life. The mechanisms leading to UFs formation and growth still remain poorly understood. The transformation of smooth muscle cells of the uterus into abnormal, immortal cells, capable of clonal division, is thought to be a starting point of all pathways leading to UF formation. Micro-ribonucleic acids (miRNAs) are non-coding single-stranded RNAs about 22 nucleotides in length, that regulate gene expression. One of recent advances in this field is the comprehension of the role of miRNAs in tumorigenesis. Alterations in the levels of miRNAs are related to the formation and growth of several tumors which show a distinct miRNA signature. The aim of this review is to summarize the current data about the role of miRNAs in the pathophysiology of UFs. We also discuss future directions in the miRNA research area with an emphasis on novel diagnostic opportunities or patient-tailored therapies. In our opinion data concerning the regulation of miRNA and its gene targets in the UFs are still insufficient in comparison with gynecological malignancies. The potential translational use of miRNA and derived technologies in the clinical care is at the early phase and needs far more evidence. However, it is one of the main areas of interest for the future as the use of miRNAs in the diagnostics and treatment of UFs is a new and exciting opportunity.

Understanding the Impact of Uterine Fibroids on Human Endometrium Function

“…It is important to highlight that miRNAs target genes involved in cell growth (miRNA-21/TGF-β), ECM remodeling (miRNA-29/COL1A1 and COL3A), angiogenesis (miRNA-200c, VEGF), and inflammation (miRNA-93/IL-8), leading to complex regulatory networks in UFs that can affect the endometrium ( Chuang et al, 2012a , b ; Karmon et al, 2014 ; Ciebiera et al, 2020 ). Furthermore, steroid hormone signaling, which is crucial in both UF development and endometrial function, regulates miRNAs and vice versa ( Klinge, 2009 ; Yuan et al, 2015 ; Gilam et al, 2017 ).…”

Macrophages and Immune Responses in Uterine Fibroids

“…In particular, uterine leiomyomas have been shown to present a dysregulation about a lot of different microRNAs and, among them also let7, miR-21, miR-93, miR-106b, and miR-200 and their predicted target genes. In addition, the same type of dysregulation has not been found in the healthy myometrium [ 68 , 72 , 73 , 74 , 75 , 76 , 77 , 78 ]. In addition, other potential gene-markers for the uterine leiomyoma can be provided through the use of gene set enrichment analysis [ 79 ].…”

Bazı Psikiyatrik ve Nörodejeneratif Bozuklukların Tanısında Potansiyel Bir Biyobelirteç MikroRNA’ ların İncelenmesi

“…RNAs are generally classified according to their nucleotide lengths. [13] miRNA is a non-coding RNA that has a role in modulating the coding potential of a replicated messenger RNA (mRNA) based on characteristic sequence complementarity. In the first report as an epigenetic modifier, miRNA is thought to work as a modulator of a single protein coding gene, while today it is known to act as a potential regulatory center in controlling a complex gene network either directly through a protein coding gene or indirectly.…”

“…miRNAs are copied from genes scattered across all chromosomes, except the Y chromosome. [13] Although small molecules and have the potential to go through exon-coupling to create more structural diversity, miRNAs show functional diversity by targeting various RNA molecules ranging from protein-encoding (mRNA) to noncoding RNAs. In humans, up to now ~2500 mature miRNAs have been disclosed, and about 30% of them have been found in intronic regions of protein coding genes, sometimes promoting the facultative use of host gene transcription machines.…”

“…In this way, it all starts in the cell nucleus, where the miRNA gene is copied by RNA polymerase II/III to the primary miRNA, which is a hairpin ring. [13] Within cell nuclei, immediately after transcription, pri-miRNAs are separated into precursor miRNAs by Drosha ribonuclease III (DROSHA) and microprocessor complex subunit DGCR8. [15] All other processes are located outside the nucleus because this leading miRNA molecule is transported into the cytoplasm using exportin 5.…”