MIR503HG silencing promotes endometrial stromal cell progression and metastasis and suppresses apoptosis in adenomyosis by activating the Wnt/β‑catenin pathway via targeting miR‑191

Xu,Xiaoping; Cai,Bin; Liu,Yang; Liu,Ruiqian; Li,Jia

doi:10.3892/etm.2023.11816

MIR503HG silencing promotes endometrial stromal cell progression and metastasis and suppresses apoptosis in adenomyosis by activating the Wnt/β‑catenin pathway via targeting miR‑191

Authors:
- Xiaoping Xu
- Bin Cai
- Yang Liu
- Ruiqian Liu
- Jia Li
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Affiliations: Department of Gynecology, People's Hospital of Deyang City, Deyang, Sichuan 618000, P.R. China, Department of Gynecology, Guizhou Province Maternal and Child Health Hospital, Guiyang, Guizhou 550000, P.R. China
Published online on: January 30, 2023 https://doi.org/10.3892/etm.2023.11816
Article Number: 117
Copyright: © Xu et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

MIR503HG is a 786 bp long lncRNA located on chromosome Xq26.3, and it can regulate diverse cellular processes. The pathogenesis of adenomyosis (AD) is associated with endometrial stromal cells (ESCs). The present study investigated the specific role of MIR503HG in AD pathogenesis and progression using ESCs derived from the endometrium of patients with AD as a model. Expression of MIR503HG and microRNA (miR)‑191 were assessed using reverse transcription‑quantitative PCR. An immunocytochemistry assay was used to detect cytokeratin‑ or vimentin‑positive ESCs. Transfections of ESCs with MIR503HG overexpression plasmid, short hairpin‑MIR503HG and miR‑191 inhibitor were performed. ESC viability, migration, invasion and apoptosis were evaluated using Cell Counting Kit‑8, Transwell and flow cytometry assays. The association between MIR503HG and miR‑191 was predicted by StarBase and confirmed using a dual‑luciferase reporter assay. Expression of epithelial‑mesenchymal transition‑related markers (E‑cadherin and N‑cadherin) and Wnt/β‑catenin pathway‑related molecules (β‑catenin) in ESCs were analyzed by western blotting. The isolated ESCs were vimentin‑positive and cytokeratin‑negative. MIR503HG was lowly expressed in the endometrial tissues derived from patients with AD. MIR503HG overexpression hindered ESC viability, migration and invasion while enhancing the apoptosis and downregulating miR‑191 expression. MIR503HG knockdown induced the opposite effects, accompanied by downregulation of the E‑cadherin expression and upregulation of N‑cadherin and β‑catenin levels. MIR503HG directly targeted miR‑191 that was highly expressed in endometrial tissues derived from patients with AD. In ESCs, downregulation of miR‑191 inhibited the viability, migration and invasion and the expression of N‑cadherin and β‑catenin levels while enhancing the apoptosis and E‑cadherin expression in ESCs. Moreover, downregulation of miR‑191 partially reversed the effect of MIR503HG knockdown. Collectively, overexpressed MIR503HG impeded the proliferation and migration of ESCs derived from endometrium of patients with AD, while promoting apoptosis via inhibition of the Wnt/β‑catenin pathway via targeting miR‑191.

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1	Ferenczy A: Pathophysiology of adenomyosis. Hum Reprod Update. 4:312–322. 1998.PubMed/NCBI View Article : Google Scholar
2	Lacheta J: Uterine adenomyosis: Pathogenesis, diagnostics, symptomatology and treatment. Ceska Gynekol. 84:240–246. 2019.PubMed/NCBI
3	Leyendecker G, Bilgicyildirim A, Inacker M, Stalf T, Huppert P, Mall G, Böttcher B and Wildt L: Adenomyosis and endometriosis. Re-visiting their association and further insights into the mechanisms of auto-traumatisation. An MRI study. Arch Gynecol Obstet. 291:917–932. 2015.PubMed/NCBI View Article : Google Scholar
4	Harada T, Khine YM, Kaponis A, Nikellis T, Decavalas G and Taniguchi F: The impact of adenomyosis on women's fertility. Obstet Gynecol Surv. 71:557–568. 2016.PubMed/NCBI View Article : Google Scholar
5	Peric H and Fraser IS: The symptomatology of adenomyosis. Best Pract Res Clin Obstet Gynaecol. 20:547–555. 2006.PubMed/NCBI View Article : Google Scholar
6	Vannuccini S and Petraglia F: Recent advances in understanding and managing adenomyosis. F1000Rese. 8(F1000)2019.PubMed/NCBI View Article : Google Scholar
7	Khalifa MA, Atri M, Klein ME, Ghatak S and Murugan P: Adenomyosis as a confounder to accurate endometrial cancer staging. Semin Ultrasound CT MR. 40:358–363. 2019.PubMed/NCBI View Article : Google Scholar
8	Yuan H and Zhang S: Malignant transformation of adenomyosis: Literature review and meta-analysis. Arch Gynecol Obstet. 299:47–53. 2019.PubMed/NCBI View Article : Google Scholar
9	Vannuccini S, Luisi S, Tosti C, Sorbi F and Petraglia F: Role of medical therapy in the management of uterine adenomyosis. Fertil Steril. 109:398–405. 2018.PubMed/NCBI View Article : Google Scholar
10	Jiang JF, Sun AJ, Xue W, Deng Y and Wang YF: Aberrantly expressed long noncoding RNAs in the eutopic endometria of patients with uterine adenomyosis. Eur J Obstet Gynecol Reprod Biol. 199:32–37. 2016.PubMed/NCBI View Article : Google Scholar
11	Zhou C, Zhang T, Liu F, Zhou J, Ni X, Huo R and Shi Z: The differential expression of mRNAs and long noncoding RNAs between ectopic and eutopic endometria provides new insights into adenomyosis. Mol Biosyst. 12:362–370. 2016.PubMed/NCBI View Article : Google Scholar
12	Bhan A, Soleimani M and Mandal SS: Long noncoding RNA and cancer: A new paradigm. Cancer Res. 77:3965–3981. 2017.PubMed/NCBI View Article : Google Scholar
13	Liang N, Zhang W, Wang H, Shi W, Wang L and Ma L: Levonorgestrel ameliorates adenomyosis via lncRNA H19/miR-17/TLR4 pathway. Drug Des Devel Ther. 14:3449–3460. 2020.PubMed/NCBI View Article : Google Scholar
14	Xu XY, Zhang J, Qi YH, Kong M, Liu SA and Hu JJ: Linc-ROR promotes endometrial cell proliferation by activating the PI3K-Akt pathway. Eur Rev Med Pharmacol Sci. 22:2218–2225. 2018.PubMed/NCBI View Article : Google Scholar
15	Fiedler J, Baker AH, Dimmeler S, Heymans S, Mayr M and Thum T: Non-coding RNAs in vascular disease-from basic science to clinical applications: scientific update from the working group of myocardial function of the european society of cardiology. Cardiovasc Res. 114:1281–1286. 2018.PubMed/NCBI View Article : Google Scholar
16	Tang H, Wu Z, Zhang Y, Xia T, Liu D, Cai J and Ye Q: Identification and function analysis of a five-long noncoding RNA prognostic signature for endometrial cancer patients. DNA Cell Biol. 38:1480–1498. 2019.PubMed/NCBI View Article : Google Scholar
17	Cheng D, Jiang S, Chen J, Li J, Ao L and Zhang Y: The increased lncRNA MIR503HG in preeclampsia modulated trophoblast cell proliferation, invasion, and migration via regulating matrix metalloproteinases and NF-κB signaling. Dis Markers. 2019(4976845)2019.PubMed/NCBI View Article : Google Scholar
18	Fu J, Dong G, Shi H, Zhang J, Ning Z, Bao X, Liu C, Hu J, Liu M and Xiong B: LncRNA MIR503HG inhibits cell migration and invasion via miR-103/OLFM4 axis in triple negative breast cancer. J Cell Mol Med. 23:4738–4745. 2019.PubMed/NCBI View Article : Google Scholar
19	Parrott E, Butterworth M, Green A, White IN and Greaves P: Adenomyosis-a result of disordered stromal differentiation. Am J Pathol. 159:623–630. 2001.PubMed/NCBI View Article : Google Scholar
20	Borisov E, Knyazeva M, Novak V, Zabegina L, Prisyazhnaya T, Karizkiy A, Berlev I and Malek A: Analysis of reciprocally dysregulated miRNAs in eutopic endometrium is a promising approach for low invasive diagnostics of adenomyosis. Diagnostics (Basel). 10(782)2020.PubMed/NCBI View Article : Google Scholar
21	Hu YL, Zhang YX, Liu N, Liu H and Yuan YC: LncRNA MIR503HG regulated cell viability, metastasis and apoptosis of cervical cancer via miR-191/CEBPB axis. Eur Rev Med Pharmacol Sci. 25:3200–3210. 2021.PubMed/NCBI View Article : Google Scholar
22	Li J, Yanyan M, Mu L, Chen X and Zheng W: The expression of Bcl-2 in adenomyosis and its effect on proliferation, migration, and apoptosis of endometrial stromal cells. Pathol Res Pract. 215(152477)2019.PubMed/NCBI View Article : Google Scholar
23	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001.PubMed/NCBI View Article : Google Scholar
24	Xu W, Ji J, Xu Y, Liu Y, Shi L, Liu Y, Lu X, Zhao Y, Luo F and Wang B: MicroRNA-191, by promoting the EMT and increasing CSC-like properties, is involved in neoplastic and metastatic properties of transformed human bronchial epithelial cells. Mol Carcinog. 54 (Suppl 1):E148–E161. 2015.PubMed/NCBI View Article : Google Scholar
25	Feng T, Wei S, Wang Y, Fu X, Shi L, Qu L and Fan X: Rhein ameliorates adenomyosis by inhibiting NF-κB and β-Catenin signaling pathway. Biomed Pharmacother. 94:231–237. 2017.PubMed/NCBI View Article : Google Scholar
26	Vercellini P, Bonfanti I and Berlanda N: Adenomyosis and infertility: Is there a causal link? Expert Rev Endocrinol Metab. 14:365–367. 2019.PubMed/NCBI View Article : Google Scholar
27	Hashimoto A, Iriyama T, Sayama S, Nakayama T, Komatsu A, Miyauchi A, Nishii O, Nagamatsu T, Osuga Y and Fujii T: Adenomyosis and adverse perinatal outcomes: Increased risk of second trimester miscarriage, preeclampsia, and placental malposition. J Matern Fetal Neonatal Med. 31:364–369. 2018.PubMed/NCBI View Article : Google Scholar
28	Shin YJ, Kwak DW, Chung JH, Kim MY, Lee SW and Han YJ: The risk of preterm births among pregnant women with adenomyosis. J Ultrasound Med. 37:1937–1943. 2018.PubMed/NCBI View Article : Google Scholar
29	Aleksandrovych V, Basta P and Gil K: Current facts constituting an understanding of the nature of adenomyosis. Adv Clin Exp Med. 28:839–846. 2019.PubMed/NCBI View Article : Google Scholar
30	Dueholm M: Uterine adenomyosis and infertility, review of reproductive outcome after in vitro fertilization and surgery. Acta Obstet Gynecol Scand. 96:715–726. 2017.PubMed/NCBI View Article : Google Scholar
31	Fiedler J, Breckwoldt K, Remmele CW, Hartmann D, Dittrich M, Pfanne A, Just A, Xiao K, Kunz M, Müller T, et al: Development of long noncoding RNA-based strategies to modulate tissue vascularization. J Am Coll Cardiol. 66:2005–2015. 2015.PubMed/NCBI View Article : Google Scholar
32	Muys BR, Lorenzi JC, Zanette DL, Lima e Bueno Rde B, de Araújo LF, Dinarte-Santos AR, Alves CP, Ramão A, de Molfetta GA, Vidal DO and Silva WA Jr: Placenta-enriched LincRNAs MIR503HG and LINC00629 decrease migration and invasion potential of JEG-3 cell line. PLoS One. 11(e0151560)2016.PubMed/NCBI View Article : Google Scholar
33	Li Y, Zhang Q, Liu F, Zhang Z, Zou Y, Yang B, Luo Y, Wang L and Huang O: Inhibition of formin like 2 promotes the transition of ectopic endometrial stromal cells to epithelial cells in adenomyosis through a MET-like process. Gene. 710:186–192. 2019.PubMed/NCBI View Article : Google Scholar
34	Cao X and Fan QL: LncRNA MIR503HG promotes high-glucose-induced proximal tubular cell apoptosis by targeting miR-503-5p/Bcl-2 pathway. Diabetes Metab Syndr Obes. 13:4507–4517. 2020.PubMed/NCBI View Article : Google Scholar
35	Lee JM, Dedhar S, Kalluri R and Thompson EW: The epithelial-mesenchymal transition: new insights in signaling, development, and disease. J Cell Biol. 172:973–981. 2006.PubMed/NCBI View Article : Google Scholar
36	Yang J and Weinberg RA: Epithelial-mesenchymal transition: At the crossroads of development and tumor metastasis. Dev Cell. 14:818–829. 2008.PubMed/NCBI View Article : Google Scholar
37	Zheng D, Duan H, Wang S, Xu Q, Gan L, Li J and Dong Q: FAK regulates epithelial-mesenchymal transition in adenomyosis. Mol Med Rep. 18:5461–5472. 2018.PubMed/NCBI View Article : Google Scholar
38	Zhang C, Wang P, Mohammed A, Zhou Z, Zhang S, Ni S and Tang Z: Function of adipose-derived mesenchymal stem cells in monocrotaline-induced pulmonary arterial hypertension through miR-191 via regulation of BMPR2. Biomed Res Int. 2019(2858750)2019.PubMed/NCBI View Article : Google Scholar
39	Oh SJ, Shin JH, Kim TH, Lee HS, Yoo JY, Ahn JY, Broaddus RR, Taketo MM, Lydon JP, Leach RE, et al: β-Catenin activation contributes to the pathogenesis of adenomyosis through epithelial-mesenchymal transition. J Pathol. 231:210–222. 2013.PubMed/NCBI View Article : Google Scholar