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.

Keywords: Endometrial cancer; Epigenetics; Methylation; MicroRNA; miR-129-2; miR-130a/b; miR-182; miR-191; miR-200b; miR-230.

Figure 1

PRISMA flow diagram.

Figure 2

MicroRNA (miRNA) as epigenetic modifiers in endometrial cancer. Schematic summary of the three epigenetic mechanisms known to involve miRNAs. (A) miRNAs can act as tumor suppressors or as oncomiRNAs. miR-200 binds directly to PTEN resulting in the inhibition of apoptosis. miR-182 binds directly to LRIG2 leading to inhibition of cell growth while the miR-182-mediated decrease in cullin-5 protein levels results in increased cell proliferation. (B) CpG-rich domains of miRNA loci can be hypo- or hyper-methylated. Hyper-methylation of the miR-129-2 locus leads to decreased expression of this miRNA, which acts as a natural inhibitor of the SOX4 oncogene, thereby activating SOX4. (C) TET1 expression is downregulated by miR-191 through the mRNA-miRNA interaction in the 3’-untranslated region of TET1. Downregulation of the TET1 protein is accompanied by hyper-methylation of the promotor region of tumor suppressors like adenomatous polyposis coli (APC), resulting in decreased gene expression and attenuated levels of APC protein.