MicroRNA‑202 inhibits endometrial stromal cell migration and invasion by suppressing the K‑Ras/Raf1/MEK/ERK signaling pathway

Abstract

The enhanced migratory ability of endometrial stromal cells (ESCs) is a key factor in the formation of functional endometrium-like tissues outside the uterine cavity during endometriosis (EMS). Although accumulating evidence has suggested the importance of microRNAs (miRNAs) in the pathogenesis of EMS, the role of particular miRNAs in the invasiveness of ESCs remain poorly understood. In the present study, the function of miRNAs in the invasiveness of ESCs, along with the associated underlying mechanism involved, were investigated. Initially, the expression patterns of miRNAs in the ectopic and eutopic endometrium isolated from patients with EMS were analyzed using microarray. MicroRNA-202-5p (miR-202) was selected for further study due to its previously reported suppressive effects on the invasion in various types of cancers. The expression of miR-202 and K-Ras in eutopic and ectopic endometrioma tissues were detected using reverse transcription-quantitative PCR, immunohistochemistry and western blotting. The migration and invasion ability of ESCs was determined using wound healing and Transwell invasion assays, respectively. Compared with that from healthy individuals, miR-202 expression was demonstrated to be lower in the eutopic endometrium from patients with EMS, which was even lower in ectopic endometrium. Functional experiments in primary ESCs revealed that enhanced miR-202 expression suppressed the cell invasion and migration abilities, which was also accompanied with increased E-cadherin and reduced N-cadherin expression in ESCs, suggesting its potentially suppressive role in epithelial-mesenchymal transition. K-Ras is a well-known regulator of the ERK signaling pathway that was shown to be directly targeted and negatively regulated by miR-202. In addition, K-Ras expression was found to be upregulated in the ectopic endometrium, where it correlated negatively with that of miR-202. Knocking down K-Ras expression mimicked the anti-invasive effects of miR-202 overexpression on ESCs, whilst K-Ras overexpression attenuated the inhibitory role of miR-202 overexpression in ESC invasion. The K-Ras/Raf1/MEK/ERK signaling pathway was also blocked by miR-202 overexpression. These findings suggested that miR-202 inhibited ESC migration and invasion by inhibiting the K-Ras/Raf1/MEK/ERK signaling pathway, rendering miR-202 a candidate for being a therapeutic target for EMS.

The microRNA-202 as a Diagnostic Biomarker and a Potential Tumor Suppressor

“…On the other hand, in NSCLC cells, overexpression of miR-202 was found to inhibit the Ras/mitogen activated protein kinase (MAPK) pathway via targeting the KRAS gene, thereby expanding apoptosis signaling induced by cisplatin [ 47 ]. This aligns with the observation that endometrial stromal cell migration and invasion is suppressed by the K-Ras/Raf1/MEK/ERK signaling pathway [ 93 ]. Additionally, ionizing radiation (IR) was reported to activate K-Ras/ERK signaling downregulated miR-202 and miR-185 expression, which, in turn, upregulated CD44.…”

Causal association of immune cells and endometriosis: a Mendelian randomization study

“…B cells expressing CD25 spontaneously secrete immunoglobulins of the IgA, IgG and IgM subclasses and have an enhanced migratory capacity compared to CD25(-) B cells ( 55 ). The increased migratory capacity of endometrial stromal cells (ESCs) is a fundamental determinant in the development of functional endometrium-like tissue outside the uterine cavity in EMS ( 56 ).…”

The Tpl2‐MEK pathway plays a critical role in spheroid‐cultured endometriotic stromal cells

“…31 Recently, reduced expression of miR-202 in patients with endometriosis has been shown to promote the migration and infiltration of endometriotic cells through the activation of K-Ras-Raf-1-MEK. 32 In addition, MEK and AKT are involved in the proliferation of endometriotic stromal cells, and the combined use of an MEK inhibitor and an AKT inhibitor results in additive inhibition of endometriotic stromal cell proliferation. 33 In the present study, upregulation of both TNFR1 and TNFR2 was observed.…”