miR‑143‑3p inhibits endometriotic stromal cell proliferation and invasion by inactivating autophagy in endometriosis

Yang,Hong; Hu,Tianqi; Hu,Panwei; Qi,Cong; Qian,Lin

doi:10.3892/mmr.2021.11995

miR‑143‑3p inhibits endometriotic stromal cell proliferation and invasion by inactivating autophagy in endometriosis

Authors:
- Hong Yang
- Tianqi Hu
- Panwei Hu
- Cong Qi
- Lin Qian
View Affiliations

Affiliations: Department of Gynaecology, Shanghai Shuguang Hospital Affiliated to Shanghai University of Traditional Chinese Medicine, Shanghai 201203, P.R. China
Published online on: March 12, 2021 https://doi.org/10.3892/mmr.2021.11995
Article Number: 356
Copyright: © Yang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Endometriosis (EM) is a multifactorial and debilitating chronic benign gynecological disease, but the pathogenesis of the disease is not completely understood. Dysregulated expression of microRNAs (miRNA/miR) is associated with the etiology of EM due to their role in regulating endometrial stromal cell proliferation and invasion. The present study aimed to identify the functions and mechanisms underlying miR‑143‑3p in EM. To explore the role of miR‑143‑3p in EM, functional miRNAs were analyzed via bioinformatics analysis. miR‑143‑3p expression levels in endometriotic stromal cells (ESCs) and normal endometrial stromal cells (NESCs) were measured via reverse transcription‑quantitative PCR. The role of miR‑143‑3p in regulating ESC proliferation and invasion was assessed by performing Cell Counting Kit‑8 and Transwell assays, respectively. miR‑143‑3p expression was significantly upregulated in ESCs compared with NESCs. Functionally, miR‑143‑3p overexpression inhibited ESC proliferation and invasion, whereas miR‑143‑3p knockdown promoted ESC proliferation and invasion. Moreover, miR‑143‑3p inhibited autophagy activation in ESCs, as indicated by decreased green puncta, which represented autophagic vacuoles, decreased microtubule associated protein 1 light chain 3α expression and increased p62 expression in the miR‑143‑4p mimic group compared with the control group. Moreover, compared with the control group, miR‑143‑3p overexpression significantly decreased the expression levels of autophagy‑related 2B (ATG2B), a newly identified target gene of miR‑143‑3p, in ESCs. ATG2B overexpression reversed miR‑143‑3p overexpression‑mediated inhibition of ESC proliferation and invasion. Collectively, the results of the present study suggested that miR‑143‑3p inhibited EM progression, thus providing a novel target for the development of therapeutic agents against EM.

View Figures

View References

1	Eskenazi B and Warner ML: Epidemiology of endometriosis. Obstet Gynecol Clin North Am. 24:235–258. 1997. View Article : Google Scholar : PubMed/NCBI
2	Simoens S, Dunselman G, Dirksen C, Hummelshoj L, Bokor A, Brandes I, Brodszky V, Canis M, Colombo GL, DeLeire T, et al: The burden of endometriosis: Costs and quality of life of women with endometriosis and treated in referral centres. Hum Reprod. 27:1292–1299. 2012. View Article : Google Scholar : PubMed/NCBI
3	Shafrir AL, Farland LV, Shah DK, Harris HR, Kvaskoff M, Zondervan K and Missmer SA: Risk for and consequences of endometriosis: A critical epidemiologic review. Best Pract Res Clin Obstet Gynaecol. 51:1–15. 2018. View Article : Google Scholar : PubMed/NCBI
4	Friend DR: Drug delivery for the treatment of endometriosis and uterine fibroids. Drug Deliv Transl Res. 7:829–839. 2017. View Article : Google Scholar : PubMed/NCBI
5	Vishnoi A and Rani S: miRNA biogenesis and regulation of diseases: An overview. Methods Mol Biol. 1509:1–10. 2017. View Article : Google Scholar : PubMed/NCBI
6	Arora S, Rana R, Chhabra A, Jaiswal A and Rani V: miRNA-transcription factor interactions: A combinatorial regulation of gene expression. Mol Genet Genomics. 288:77–87. 2013. View Article : Google Scholar : PubMed/NCBI
7	Filigheddu N, Gregnanin I, Porporato PE, Surico D, Perego B, Galli L, Patrignani C, Graziani A and Surico N: Differential expression of microRNAs between eutopic and ectopic endometrium in ovarian endometriosis. J Biomed Biotechnol. 2010:3695492010. View Article : Google Scholar : PubMed/NCBI
8	Zhao L, Gu C, Ye M, Zhang Z, Li L, Fan W and Meng Y: Integration analysis of microRNA and mRNA paired expression profiling identifies deregulated microRNA-transcription factor-gene regulatory networks in ovarian endometriosis. Reprod Biol Endocrinol. 16:42018. View Article : Google Scholar : PubMed/NCBI
9	Shi H, Shen H, Xu J, Zhao S, Yao S and Jiang N: MiR-143-3p suppresses the progression of ovarian cancer. Am J Transl Res. 10:866–874. 2018.PubMed/NCBI
10	Deng L, Blanco FJ, Stevens H, Lu R, Caudrillier A, McBride M, McClure JD, Grant J, Thomas M, Frid M, et al: MicroRNA-143 Activation regulates smooth muscle and endothelial cell crosstalk in pulmonary arterial hypertension. Circ Res. 117:870–883. 2015. View Article : Google Scholar : PubMed/NCBI
11	Teague EM, Print CG and Hull ML: The role of microRNAs in endometriosis and associated reproductive conditions. Hum Reprod Update. 16:142–165. 2010. View Article : Google Scholar : PubMed/NCBI
12	Zheng B, Xue X, Zhao Y, Chen J, Xu CY and Duan P: The differential expression of microRNA-143,145 in endometriosis. Iran J Reprod Med. 12:555–560. 2014.PubMed/NCBI
13	Cosar E, Mamillapalli R, Ersoy GS, Cho S, Seifer B and Taylor HS: Serum microRNAs as diagnostic markers of endometriosis: A comprehensive array-based analysis. Fertil Steril. 106:402–409. 2016. View Article : Google Scholar : PubMed/NCBI
14	Bravo-San Pedro JM, Kroemer G and Galluzzi L: Autophagy and mitophagy in cardiovascular disease. Circ Res. 120:1812–1824. 2017. View Article : Google Scholar : PubMed/NCBI
15	Menzies FM, Fleming A, Caricasole A, Bento CF, Andrews SP, Ashkenazi A, Füllgrabe J, Jackson A, Jimenez Sanchez M, Karabiyik C, et al: Autophagy and neurodegeneration: Pathogenic mechanisms and therapeutic opportunities. Neuron. 93:1015–1034. 2017. View Article : Google Scholar : PubMed/NCBI
16	White E, Mehnert JM and Chan CS: Autophagy, metabolism, and cancer. Clin Cancer Res. 21:5037–5046. 2015. View Article : Google Scholar : PubMed/NCBI
17	Allavena G, Carrarelli P, Del Bello B, Luisi S, Petraglia F and Maellaro E: Autophagy is upregulated in ovarian endometriosis: A possible interplay with p53 and heme oxygenase-1. Fertil Steril. 103:1244–51.e1. 2015. View Article : Google Scholar : PubMed/NCBI
18	Neshkov NS: Use of ultrasound in therapy of neuroreceptor forms of impotence. Vopr Kurortol Fizioter Lech Fiz Kult. 35:2701970.(In Russian). PubMed/NCBI
19	Shi YL, Luo XZ, Zhu XY, Hua KQ, Zhu Y and Li DJ: Effects of combined 17beta-estradiol with TCDD on secretion of chemokine IL-8 and expression of its receptor CXCR1 in endometriotic focus-associated cells in co-culture. Hum Reprod. 21:870–879. 2006. View Article : Google Scholar : PubMed/NCBI
20	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. View Article : Google Scholar : PubMed/NCBI
21	Mari-Alexandre J, Sanchez-Izquierdo D, Gilabert-Estelles J, Barcelo-Molina M, Braza-Boils A and Sandoval J: miRNAs regulation and its role as biomarkers in endometriosis. Int J Mol Sci. 17:932016. View Article : Google Scholar
22	Okamoto M, Nasu K, Abe W, Aoyagi Y, Kawano Y, Kai K, Moriyama M and Narahara H: Enhanced miR-210 expression promotes the pathogenesis of endometriosis through activation of signal transducer and activator of transcription 3. Hum Reprod. 30:632–641. 2015. View Article : Google Scholar : PubMed/NCBI
23	Abdel-Rasheed M..Nour Eldeen G..Mahmoud M..El Hefnawi M..Abu-Shahba N..Reda M..Elsetohy K..Nabil M..Elnoury, et al: MicroRNA expression analysis in endometriotic serum treated mesenchymal stem cells. EXCLI journal. 16:852–867. 2017.PubMed/NCBI
24	Ohlsson Teague EM, Van der Hoek KH, Van der Hoek MB, Perry N, Wagaarachchi P, Robertson SA, Print CG and Hull LM: MicroRNA-regulated pathways associated with endometriosis. Mol Endocrinol. 23:265–275. 2009. View Article : Google Scholar : PubMed/NCBI
25	He R, Liu X, Zhang J, Wang Z, Wang W, Fu L, Fan Y, Sun S, Cao Y, Zhan L, et al: NLRC5 inhibits inflammation of secretory phase ectopic endometrial stromal cells by up-regulating autophagy in ovarian endometriosis. Front Pharmacol. 11:12812020. View Article : Google Scholar : PubMed/NCBI
26	Ding Y, Zhu Q, He Y, Lu Y, Wang Y, Qi J, Wu H, Xu R, Li J, Li X, et al: Induction of autophagy by Beclin-1 in granulosa cells contributes to follicular progesterone elevation in ovarian endometriosis. Transl Res. 227:15–29. 2021. View Article : Google Scholar : PubMed/NCBI
27	Ma W, Ding F, Wang X, Huang Q, Zhang L, Bi C, Hua B, Yuan Y, Han Z, Jin M, et al: By Targeting Atg7 MicroRNA-143 mediates oxidative stress-induced autophagy of c-Kit⁺ mouse cardiac progenitor cells. EBioMedicine. 32:182–191. 2018. View Article : Google Scholar : PubMed/NCBI
28	Lin XT, Zheng XB, Fan DJ, Yao QQ, Hu JC, Lian L, Wu XJ, Lan P and He XS: MicroRNA-143 targets ATG2B to inhibit autophagy and increase inflammatory responses in Crohn's disease. Inflamm Bowel Dis. 24:781–791. 2018. View Article : Google Scholar : PubMed/NCBI
29	Wei J, Ma Z, Li Y, Zhao B, Wang D and Jin Y and Jin Y: miR-143 inhibits cell proliferation by targeting autophagy-related 2B in non-small cell lung cancer H1299 cells. Mol Med Rep. 11:571–576. 2015. View Article : Google Scholar : PubMed/NCBI
30	Gao S, Wang K and Wang X: miR-375 targeting autophagy-related 2B (ATG2B) suppresses autophagy and tumorigenesis in cisplatin-resistant osteosarcoma cells. Neoplasma. 67:724–734. 2020. View Article : Google Scholar : PubMed/NCBI
31	Tanbo T and Fedorcsak P: Endometriosis-associated infertility: Aspects of pathophysiological mechanisms and treatment options. Acta Obstet Gynecol Scand. 96:659–667. 2017. View Article : Google Scholar : PubMed/NCBI
32	Ahn SH, Monsanto SP, Miller C, Singh SS, Thomas R and Tayade C: Pathophysiology and immune dysfunction in endometriosis. BioMed Res Int. 2015:7959762015. View Article : Google Scholar : PubMed/NCBI
33	Králíčková M and Vetvicka V: Immunological aspects of endometriosis: A review. Ann Transl Med. 3:1532015.PubMed/NCBI
34	Olovsson M: Immunological aspects of endometriosis: An update. Am J Reprod Immunol. 66 (Suppl 1):101–104. 2011. View Article : Google Scholar : PubMed/NCBI
35	Filippi I, Carrarelli P, Luisi S, Batteux F, Chapron C, Naldini A and Petraglia F: Different expression of hypoxic and angiogenic factors in human endometriotic lesions. Reprod Sci. 23:492–497. 2016. View Article : Google Scholar : PubMed/NCBI
36	Zhan L, Wang W, Zhang Y, Song E, Fan Y and Wei B: Hypoxia-inducible factor-1alpha: A promising therapeutic target in endometriosis. Biochimie. 123:130–137. 2016. View Article : Google Scholar : PubMed/NCBI
37	Tsuzuki T, Okada H, Cho H, Tsuji S, Nishigaki A, Yasuda K and Kanzaki H: Hypoxic stress simultaneously stimulates vascular endothelial growth factor via hypoxia-inducible factor-1α and inhibits stromal cell-derived factor-1 in human endometrial stromal cells. Hum Reprod. 27:523–530. 2012. View Article : Google Scholar : PubMed/NCBI
38	Daskalaki I, Gkikas I and Tavernarakis N: Hypoxia and selective autophagy in cancer development and therapy. Front Cell Dev Biol. 6:1042018. View Article : Google Scholar : PubMed/NCBI
39	Liu W, Meng Y, Zong C, Zhang S and Wei L: Autophagy and tumorigenesis. Adv Exp Med Biol. 1207:275–299. 2020. View Article : Google Scholar : PubMed/NCBI
40	White E: The role for autophagy in cancer. J Clin Invest. 125:42–46. 2015. View Article : Google Scholar : PubMed/NCBI
41	Leyendecker G, Kunz G, Noe M, Herbertz M and Mall G: Endometriosis: A dysfunction and disease of the archimetra. Hum Reprod Update. 4:752–762. 1998. View Article : Google Scholar : PubMed/NCBI
42	Ruiz A, Rockfield S, Taran N, Haller E, Engelman RW, Flores I, Panina-Bordignon P and Nanjundan M: Effect of hydroxychloroquine and characterization of autophagy in a mouse model of endometriosis. Cell Death Dis. 7:e20592016. View Article : Google Scholar : PubMed/NCBI
43	Zhan L, Li J and Wei B: Autophagy in endometriosis: Friend or foe? Biochem Biophys Res Commun. 495:60–63. 2018. View Article : Google Scholar : PubMed/NCBI
44	Liu H, Zhang Z, Xiong W, Zhang L, Xiong Y, Li N, He H, Du Y and Liu Y: Hypoxia-inducible factor-1alpha promotes endometrial stromal cells migration and invasion by upregulating autophagy in endometriosis. Reproduction. 153:809–820. 2017. View Article : Google Scholar : PubMed/NCBI
45	Pei T, Huang X, Long Y, Duan C, Liu T, Li Y and Huang W: Increased expression of YAP is associated with decreased cell autophagy in the eutopic endometrial stromal cells of endometriosis. Mol Cell Endocrinol. 491:1104322019. View Article : Google Scholar : PubMed/NCBI
46	Sui X, Li Y, Sun Y, Li C, Li X and Zhang G: Expression and significance of autophagy genes LC3, Beclin1 and MMP-2 in endometriosis. Exp Ther Med. 16:1958–1962. 2018.PubMed/NCBI
47	Mei J, Zhou WJ, Zhu XY, Lu H, Wu K, Yang HL, Fu Q, Wei CY, Chang KK, Jin LP, et al: Suppression of autophagy and HCK signaling promotes PTGS2high FCGR3- NK cell differentiation triggered by ectopic endometrial stromal cells. Autophagy. 14:1376–1397. 2018. View Article : Google Scholar : PubMed/NCBI
48	Luo X, Cheng W, Wang S, Chen Z and Tan J: Autophagy suppresses invasiveness of endometrial cells through reduction of Fascin-1. BioMed Res Int. 2018:86154352018. View Article : Google Scholar : PubMed/NCBI
49	Zhao Y and Srivastava D: A developmental view of microRNA function. Trends Biochem Sci. 32:189–197. 2007. View Article : Google Scholar : PubMed/NCBI
50	Esquela-Kerscher A and Slack FJ: Oncomirs - microRNAs with a role in cancer. Nat Rev Cancer. 6:259–269. 2006. View Article : Google Scholar : PubMed/NCBI
51	Stolzenburg LR and Harris A: The role of microRNAs in chronic respiratory disease: Recent insights. Biol Chem. 399:219–234. 2018. View Article : Google Scholar : PubMed/NCBI
52	Soroosh A, Koutsioumpa M, Pothoulakis C and Iliopoulos D: Functional role and therapeutic targeting of microRNAs in inflammatory bowel disease. Am J Physiol Gastrointest Liver Physiol. 314:G256–G262. 2018. View Article : Google Scholar : PubMed/NCBI
53	Wu MH, Chen KF, Lin SC, Lgu CW and Tsai SJ: Aberrant expression of leptin in human endometriotic stromal cells is induced by elevated levels of hypoxia inducible factor-1alpha. Am J Pathol. 170:590–598. 2007. View Article : Google Scholar : PubMed/NCBI
54	Hsiao KY, Lin SC, Wu MH and Tsai SJ: Pathological functions of hypoxia in endometriosis. Front Biosci (Elite Ed). 7:309–321. 2015.PubMed/NCBI
55	Donnez J, Smoes P, Gillerot S, Casanas-Roux F and Nisolle M: Vascular endothelial growth factor (VEGF) in endometriosis. Hum Reprod. 13:1686–1690. 1998. View Article : Google Scholar : PubMed/NCBI
56	Zhang X, Liu S, Hu T, Liu S, He Y and Sun S: Up-regulated microRNA-143 transcribed by nuclear factor kappa B enhances hepatocarcinoma metastasis by repressing fibronectin expression. Hepatology. 50:490–499. 2009. View Article : Google Scholar : PubMed/NCBI