MicroRNA as Epigenetic Modifiers in Endometrial Cancer: A Systematic Review

Abstract

The objective of this systematic review is to summarize our current knowledge on the influence of miRNAs in the epigenetic deregulation of tumor-related genes in endometrial cancer (EC). We conducted a literature search on the role of miRNAs in the epigenetic regulation of EC applying the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The following terms were used: microRNA, miRNA, miR, endometrial cancer, endometrium, epigenetic, epimutation, hypermethylation, lynch, deacetylase, DICER, novel biomarker, histone, chromatin. The miRNAs were classified and are presented according to their function (tumor suppressor or onco-miRNA), their targets (when known), their expression levels in EC tissue vs the normal surrounding tissue, and the degree of DNA methylation in miRNA loci and CpG sites. Data were collected from 201 articles, including 190 original articles, published between November 1, 2008 and September 30, 2020 identifying 313 different miRNAs implicated in epigenetic regulation of EC. Overall, we identified a total of 148 miRNAs with decreased expression in EC, 140 miRNAs with increased expression in EC, and 22 miRNAs with discordant expression levels. The literature implicated different epigenetic phenomena including altered miRNA expression levels (miR-182, -230), changes in the methylation of miRNA loci (miR-34b, -129-2, -130a/b, -152, -200b, -625) and increased/decreased methylation of target genes (miR-30d,-191). This work provides an overview of all miRNAs reported to be involved in epigenetic regulation in EC including DNA methylation and RNA-associated silencing. These findings may contribute to novel strategies in diagnosis, risk assessment, and treatments aimed at miRNAs, their target genes or DNA methylation.

The Role of miRNAs in the Regulation of Endometrial Cancer Invasiveness and Metastasis—A Systematic Review

“…Further, analysis of miRNA-seq data from The Cancer Genome Atlas (TCGA) database expanded the list of dysregulated miRNAs to 531 [ 179 ]. Previous systematic reviews identified, respectively, 106 miRNAs [ 183 ], 261 miRNAs [ 184 ], 310 miRNAs [ 185 ] dysregulated in ECs. However, these studies included also many miRNAs detected by high throughput methods, including microarrays and small RNA-seq, without confirmation by the RT-qPCR method that is a gold standard for miRNAs analysis [ 186 ].…”

“…EZH2 is targeted by miR-26a and miR-101, which are downregulated in EC [42,46]. Importantly, epigenetic alterations affect miRNAs profile in EC [185]. It was found that loci of genes coding oncomiRNAs miR-130a/b, miR-182, miR-200b, miR-208a, miR-222, miR-625 are hypo-methylated in EC while genes of tumor-suppressor miRNAs miR-34b, miR-124a-1, miR-124a-2, miR-124a-3, miR-129-2, miR-137, miR-152, miR-638, miR-663 are hyper-methylated [185].…”

MicroRNAs in the Regulation of Endometrial Receptivity for Embryo Implantation

“…MiRNAs in gynaecological diseases have also been reviewed [ 60 , 61 , 62 ]. However, the endometrium has often been overlooked in reviews concerning miRNAs, except when endometrial miRNAs are related to endometriosis [ 63 , 64 , 65 , 66 , 67 , 68 , 69 , 70 ] or endometrial cancer [ 71 , 72 , 73 , 74 , 75 , 76 ]. The remainder of this paper thus focuses on miRNAs in endometrial receptivity which has not been reviewed previously.…”

Can miRNAs be useful biomarkers in improving prognostic stratification in endometrial cancer patients? An update review

“… 29 , 30 , 31 , 32 , 33 , 34 , 35 However, in most of these, especially when focused on miRNAs, deregulation was observed by comparing tumor with normal counterpart or healthy tissue. 36 In this context, among others, a complete overview is presented by Srivastava et al, who reviewed the miRNAs differentially expressed in EC with respect to normal endometrial tissue. 37 On the contrary, the studies that analyzed miRNA expression taking into account other parameters, such as grade or the existing classifications schemes, particularly the TCGA one, are limited and with small consensus.…”