miR-200c suppresses endometriosis by targeting MALAT1 in vitro and in vivo

Abstract

BackgroundEndometriosis is a common, benign, and estrogen-dependent disease characterized by pelvic pain and infertility. To date, the pathogenesis of endometriosis remains unclear. Recent studies have demonstrated that noncoding RNAs, including microRNAs and long noncoding RNAs, play important roles in the development of endometriosis.MethodsExpression profiling of miRNAs in endometrial tissue was characterized using microarrays. The most differentially expressed miRNAs were confirmed using quantitative reverse transcriptase-polymerase chain reaction analysis in additional ectopic endometrial (n = 27) and normal endometrial (n = 12) tissues. For in-vitro functional studies, 5-ethynyl-2′-deoxyuridine incorporation assay, Transwell assay, and dual-luciferase reporter assay were used to measure the proliferation, migration, and luciferase activity of miR-200c and the predicted targets of miR-200c in primary endometrial stromal cells (HESCs) derived from human endometrial biopsies, respectively. For in-vivo therapeutic interventions, polymeric nanoparticles of polyethylenimine–polyethylene glycol–arginine–glycine–aspartic acid were used for delivery of miR-200c mimic and inhibitor to determine the therapeutic effect of miR-200c in a rat model of endometriosis.ResultsExogenous overexpression of miR-200c inhibited the proliferation and migration of HESCs, which were mainly regulated by metastasis-associated lung adenocarcinoma transcript 1 (MALAT1). In contrast, inhibition of miR-200c promoted the proliferation and migration of HESCs, while the simultaneous silencing of MALAT1 expression exerted the opposite effects. We demonstrated that expression of MALAT1 in ectopic endometrial specimens was negatively correlated with that of miR-200c and that MALAT1 knockdown increased the level of miR-200c in HESCs. Moreover, the transfection of endometrial stromal cells with the miR-200c mimic or MALAT1 siRNAs decreased the protein levels of mesenchymal markers ZEB1, ZEB2, and N-cadherin and increased the protein levels of the epithelial marker E-cadherin. Furthermore, using a rat endometriosis model, we showed that local delivery of the miR-200c mimic significantly inhibited the growth of ectopic endometriotic lesions.ConclusionsThe MALAT1/miR-200c sponge may be a potential therapeutic target for endometriosis.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-017-0706-z) contains supplementary material, which is available to authorized users.

Long non‐coding RNA MALAT1 mediates hypoxia‐induced pro‐survival autophagy of endometrial stromal cells in endometriosis

“…In this study, by thorough examination of ovarian endometriosis samples, we found that levels of lncRNA‐MALAT1 were significantly overexpressed in ovarian endometriosis samples, compared with normal and eutopic endometrium of endometriosis. This result is consistent with the previous findings of Liang et al, who found that the expression level of lncRNA‐MALAT1 was significantly higher in ectopic endometrium tissue of endometriosis when compared with the paired normal endometrial tissue from the same patient . More importantly, previous studies reported that hypoxia provides an important driving factor in the expression pattern of various lncRNAs including MALAT1.…”

“…In addition, several studies reported that lncRNA‐MALAT1 modulates the activity of autophagy . More importantly, recent research indicated expression of lncRNA‐MALAT1 was significantly increased in the ectopic endometrium of patients with ovarian endometriosis . However, the correlation between lncRNA‐MALAT1 and autophagy remains unclear in the context of endometriosis.…”

Estradiol promotes EMT in endometriosis via MALAT1/miR200s sponge function

“…LncRNAs are able to post-transcriptionally regulate gene expression by competitively binding to miRNAs. A recent study has demonstrated elevated MALAT1 expression and decreased miR200c expression in endometriosis and suggested that MALAT1/miR200c may be involved in regulating EMT during the development of endometriosis (Liang et al 2017). Through RNAhybrid, miR200c was predicted to exhibit the strongest interaction with MALAT1.…”

“…LncRNA MALAT1, upregulated in several cancers, may promote the development and metastasis of tumors by promoting EMT (Xiao et al 2015, Yoshimoto et al 2016. A recent study demonstrated that expression of MALAT1 in ectopic endometrial specimens is negatively correlated with that of miR200c, while MALAT1 knockdown increased the level of miR200c in endometrial stromal cells (Liang et al 2017). The finding suggested that MALAT1/miR200c may participate in the development of endometriosis by affecting EMT.…”

NNT‐AS1 enhances bladder cancer cell growth by targeting miR‐1301‐3p/PODXL axis and activating Wnt pathway

“…26 MALAT1 was reported to increase ZEB2 expression by downregulating miR-200c expression in the network of ceRNA. 27 lncRNA NNT-AS1 has been confirmed to promote proliferation and invasion of gastric cancer cells by modulating miRNA-363 expression. 28 lncRNA NNT-AS1 sponges miR-142-3p in breast cancer and affects cancer progression by targeting ZEB1.…”