Oestrogen-induced epithelial-mesenchymal transition (EMT) in endometriosis: Aetiology of vaginal agenesis in Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome

Abstract

Endometriosis occurs when endometrial-like tissue forms and grows outside the uterus due to oestrogen-induced epithelial-mesenchymal transition in the female reproductive tract. Factors that suppress this event could become potential therapeutic agents against disease occurrence and progression. However, an overview of these studies is still lacking. This review assessed the impact of a number factors on oestrogen-mediated epithelial-mesenchymal transition in the emergence of several diseases in the female reproductive tract, primarily endometriosis. The association between epithelial-mesenchymal transition and Mayer-Rokitansky-Küster-Hauser (MRKH) syndrome was also investigated. Oestrogen, Wnt4 and epithelial-mesenchymal transition were chosen as keywords in Scopus, PubMed, and Web of Science searches performed on 28th June 2021. Study selection was refined to cancer-irrelevant, English, original articles published between years 2011-2021. The full-text assessment was carried out for topic-related articles after title and abstract screening. Included studies were summarised and assessed for their risk of bias using the Office of Health Assessment and Translation tool. In this review, 10 articles investigating oestrogen and epithelial-mesenchymal transition in the female reproductive tract were summarised and classified into two groups: seven studies under 'factor'-modulated epithelial-mesenchymal transition and three studies under 'factor'-manipulated oestrogen-induced epithelial-mesenchymal transition. The current evidence proposes that epithelial-mesenchymal transition is one of the prime causes of reproductive-related disease. This event could be mediated by distinct stimuli, specifically oestrogen and Wnt4 aberration. The results of this review suggest that oestrogen and Wnt4 participate in epithelial-mesenchymal transition in vaginal epithelial cells in MRKH syndrome, adopting from the theories of endometriosis development, which could therefore serve as a foundation for novel target treatment, specifically related to vaginal epithelialisation, to ensure better surgical outcomes.

Keywords: Mayer-Rokitansky-Küster-Hauser syndrome; Wnt4; endometriosis; epithelial-mesenchymal transition; oestrogen.

FIGURE 1

Flow chart of the study selection process from electronic databases of PubMed, Scopus, and Web of Science.

FIGURE 2

Schematic illustrating the potentiality of different stimuli in regulating EMT process with or without the association of E2 resulting in diseases-related female reproductive tract. LXA₄ inhibited EMT via ALXR-dependent manner. Melatonin upregulated Numb expression and decreased the activity of Notch1 signalling pathway to block EMT occurrence. In contrast, both NRP1 and metformin were associated to E2 in regulating EMT. Metformin modulated EMT in an E2-dependent manner. Besides that, E2 was correlated to TGF-β1, miR200c and miR-148a-3p in suppressing EMT event while upregulated MALAT1, circ_0004712, ZEB1, LPS and RhoA (via activating ERK signalling pathway) to induce EMT process. There were two pairs of stimuli, MALAT1/miR200c as well as circ_0004712/miR-148a-3p which possessed an antagonism effect between them. An example, the antagonism effect happened when circ_0004712 sponged miR-148a-3p to activate β-catenin signalling pathway, thus promoting EMT event. E2, oestrogen; EMT, epithelial-mesenchymal transition; LXA₄, lipoxin A₄; MLT, melatonin; NRP1, neurophilin 1; Met, metformin; Numb and Notch, Notch1/Numb signalling pathway; ALXR, lipoxin A₄ receptor; 200c, miR200c; 0004712, circ_0004712; 148a-3p, miR-148a-3p; LPS, lipopolysaccharide; β-catenin, β-catenin signalling pathway; ERK, ERK signalling pathway; TGF-β1, transforming growth factor-β1; ZEB1, zinc finger E-box-binding homeobox 1; RhoA, transforming protein RhoA; MALAT1, metastasis-associated lung adenocarcinoma transcript 1 (Designed with BioRender: https://biorender.com/).

FIGURE 3

Crosstalk between E2, Wnt4 and EMT in the development of EM: Aetiology of vaginal agenesis in MRKH. Pathogenesis of EM has been classically defined to originate from Mullerian-related cells expressing Wnt4 in early human development. Under the influence of E2 and other appropriate stimuli, the cells exhibit EMT and progress into endometriotic lesions in adults. Corresponding to MRKH patients which also initiated from Mullerian cells, the disorder develops when Wnt4 is mutated in coelomic epithelium of embryo. This could then trigger EMT which leads to female reproductive organ formation failure, such as vagina and uterus. E2, oestrogen; EMT, epithelial-mesenchymal transition; Wnt4, Wnt family member 4; MD, Mullerian duct; WD, Wolffian duct; MRKH, Mayer-Rokitansky-Küster-Hauser syndrome; EM, endometriosis (Designed with BioRender: https://biorender.com/).