The miRNA Mirage: How Close Are We to Finding a Non-Invasive Diagnostic Biomarker in Endometriosis? A Systematic Review

Abstract

Background: Endometriosis is a common disorder of the reproductive age group, characterised by the presence of ectopic endometrial tissue. The disease not only causes enormous suffering to the affected women, but also brings a tremendous medical and economic burden to bear on society. There is a long lag phase between the onset and diagnosis of the disease, mainly due to its non-specific symptoms and the lack of a non-invasive test. Endometriosis can only be diagnosed invasively by laparoscopy. A specific, non-invasive test to diagnose endometriosis is an unmet clinical need. The recent discovery of microRNAs (miRNAs) as modulators of gene expression, and their stability and specificity, make them an attractive candidate biomarker. Various studies on miRNAs in endometriosis have identified their cardinal role in the pathogenesis of the disease, and have proposed them as potential biomarkers in endometriosis. Rationale/Objectives: The aims of this review were to study the role of circulatory miRNAs in endometriosis, and bring to light whether circulatory miRNAs could be potential non-invasive biomarkers to diagnose the disease.

Search methods: Three databases, PubMed, EMBASE, and BIOSIS were searched, using a combination of Mesh or Emtree headings and free-text terms, to identify literature relating to circulating miRNAs in endometriosis published from 1996 to 31 December 2017. Only peer-reviewed, full-text original research articles in English were included in the current review. The studies meeting the inclusion criteria were critically assessed and checked using the QUADAS-2 (Quality Assessment of Diagnostic Accuracy Studies) tool. The dysregulated miRNAs were assessed regarding the concordance between the various studies and their role in the disease.

Outcomes: Nine studies were critically analysed, and 42 different miRNAs were found to be dysregulated in them, with only one common miRNA (miR-20a) differentially expressed in more than one study. miR-17-5p/20a, miR-200, miR-199a, miR-143, and miR-145 were explored for their pivotal role in the aetiopathogenesis of endometriosis. Wider implications: It is emerging that miRNAs play a central role in the pathogenesis of endometriosis and have the potential of being promising biomarkers. Circulating miRNAs as a non-invasive diagnostic tool may shorten the delay in the diagnosis of the disease, thus alleviating the suffering of women and reducing the burden on health care systems. However, despite numerous studies on circulating miRNAs in endometriosis, no single miRNA or any panel of them seems to meet the criteria of a diagnostic biomarker. The disagreement between the various studies upholds the demand of larger, well-controlled systematic validation studies with uniformity in the research approaches and involving diverse populations.

Keywords: biomarker; circulating; endometriosis; microRNA; non-invasive.

Figure 1

miRNAs regulate gene expression. They inhibit translation of the target messenger RNA (mRNA), and thus, repress protein synthesis.

Figure 2

Overview of microRNA (miRNA) biogenesis and function. miRNAs are transcribed as primary miRNA (pri-miRNA) in the nucleus by the RNA polymerase II (Pol II) enzyme. The pri-miRNA is then cleaved by the microprocessor complex formed by an RNase III enzyme, Drosha, and RNA binding cofactor, Pasha, to form precursor miRNA (pre-miRNA). Pri-miRNA is exported to the cytoplasm by exportin 5, where the miRNA duplex is cleaved by Dicer, and then unwound by helicase to form a 19–22 nucleotides long mature miRNA. The guide strand gets incorporated into RNA-induced silencing complex (RISC), and the complex regulates post-translational modification by binding to the target miRNA.

Figure 3

The figure schematically depicts the proposed role of miRNAs in angiogenesis and cell proliferation. ↓ indicates down-regulation and ↑ indicates up-regulation.

Figure 4

The figure schematically depicts the epithelial cells (endometrial cells) losing their polarity and cell to cell adhesion undergoing changes to assume a migratory mesenchymal cell phenotype. miR-20a and miR-200 play a crucial role in this epithelial mesenchymal transition (EMT) which also is proposed to be one of the key processes in the pathogenesis of endometriosis. ↓ indicates down-regulation and ↑ indicates up-regulation.

Figure 5

miR-200b regulates epithelial–mesenchymal transition (EMT). Downregulation of miR-200b in endometriosis upscales the translation of ZEB ½, which further inhibits E-cadherin expression on cells, and promotes EMT, contributing to the pathogenesis of endometriosis. TGF-β also promotes EMT and is found in higher levels in peritoneal endometriosis.

Figure 6

Search strategy and study selection as per PRISMA guidelines.