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Cited by 35MicroRNA in disease regulationRetinal Diseases and TreatmentsRetinal Development and Disorders

miR-194 suppresses epithelial-mesenchymal transition of retinal pigment epithelial cells by directly targeting ZEB1

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Cui, Lian, Lyu, Yali, Jin, Xiaoliang, Wang, Yueye, Li, Xiang, Wang, Juan, Zhang, Jieping, Deng, Zhongzhu +12 more·2019·Annals of Translational Medicine
DOI 10.21037/atm.2019.11.90PMC PMC6990010
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Abstract

Background: Epithelial-mesenchymal transition (EMT) of the retinal pigment epithelial (RPE) cells is a critical step in the pathogenesis of proliferative vitreoretinopathy (PVR). Some microRNAs (miRNAs) participate in regulating RPE cell EMT as post-transcriptional regulators. However, the function of miR-194 in RPE cell EMT remains elusive. Here, the role of miR-194 in PVR was investigated. Methods: Retinal layers were obtained using laser capture microdissection (LCM). Gene expression at the mRNA and protein level in the tissues and cells was examined using quantitative reverse transcription (RT)-polymerase chain reaction and Western blotting, respectively. The related protein expression was observed by immunostaining. The effect of miR-194 on RPE cell EMT was examined by gel contraction, wound healing, and cell migration assays. RNAseq was performed in ARPE-19 with transfection of pSuper-scramble and pSuper-miR-194. The target gene of miR-194 was identified and confirmed via bioinformatics analysis and dual-luciferase reporter assay. ARPE-19 (adult retinal pigment epithelium-19) cells were treated with transforming growth factor (TGF)-β1 in the same fashion as the in vitro RPE cell EMT model. A PVR rat model was prepared by intravitreous injection of ARPE-19 cells with plasma-rich platelets. Results: miR-194 was preferentially expressed in the RPE cell layer compared with the outer nuclear layer (ONL), inner nuclear layer (INL), and ganglion cell layer in rat retina. RNAseq analysis indicated that miR-194 overexpression was involved in RPE cell processes, including phagocytosis, ECM-receptor interaction, cell adhesion molecules, and focal adhesion. miR-194 overexpression significantly inhibited the TGF-β1-induced EMT phenotype of RPE cells in vitro. Zinc finger E-box binding homeobox 1 (ZEB1), a key transcription factor in EMT, was confirmed as the direct functional target of miR-194. Knockdown of ZEB1 attenuated TGF-β1-induced α-smooth muscle actin expression in ARPE-19 cells, and overexpression of miR-194 could significantly reduce the expression of some genes which were up-regulated by ZEB1. Exogenous miR-194 administration in vivo effectively suppressed PVR in the rat model, both functionally and structurally. Conclusions: Our findings demonstrate for the first time that miR-194 suppresses RPE cell EMT by functionally targeting ZEB1. The clinical application of miR-194 in patients with PVR merits further investigation.

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  • miR-194 is physiologically expressed in rat RPE, targets ZEB1, and exogenous administration of miR-194 alleviates proliferative vitreoretinopathy.

    “MiR-194 is physiologically expressed in rat RPE. It targets zinc finger E-box binding homeobox 1 (ZEB1) and is in silico predicted to regulate numerous cell functions, among others, phagocytosis. Indeed, exogenous administration of miR-194 alleviates proliferative vitreoretinopathy [267].”

    From MicroRNAs as Regulators of Phagocytosis (2022) · cites this paper as [267]

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Research works printed but not linked: 44

  1. Sadaka A, Giuliari GP. Proliferative vitreoretinopathy: current and emerging treatments. Clin Ophthalmol 2012;6:1325-33.
  2. Nemet A, Moshiri A, Yiu G, et al. A Review of Innovations in Rhegmatogenous Retinal Detachment Surgical Techniques. J Ophthalmol 2017;2017:4310643.
  3. Tamiya S, Liu L, Kaplan HJ. Epithelial-mesenchymal transition and proliferation of retinal pigment epithelial cells initiated upon loss of cell-cell contact. Invest Ophthalmol Vis Sci 2010;51:2755-63.
  4. Banerjee S, Savant V, Scott RA, et al. Multiplex bead analysis of vitreous humor of patients with vitreoretinal disorders. Invest Ophthalmol Vis Sci 2007;48:2203-7.
  5. Baudouin C, Fredj-Reygrobellet D, Brignole F, et al. Growth factors in vitreous and subretinal fluid cells from patients with proliferative vitreoretinopathy. Ophthalmic Res 1993;25:52-9.
  6. Canataroglu H, Varinli I, Ozcan AA, et al. Interleukin (IL)- 6, interleukin (IL)-8 levels and cellular composition of the vitreous humor in proliferative diabetic retinopathy, proliferative vitreoretinopathy, and traumatic proliferative vitreoretinopathy. Ocul Immunol Inflamm 2005;13:375-81.
  7. Asaria RH, Kon CH, Bunce C, et al. Silicone oil concentrates fibrogenic growth factors in the retro-oil fluid. Br J Ophthalmol 2004;88:1439-42.
  8. Kim IK, Arroyo JG. Mechanisms in proliferative vitreoretinopathy. Ophthalmol Clin North Am 2002;15:81-6.
  9. Kalluri R, Weinberg RA. The basics of epithelial- mesenchymal transition. J Clin Invest 2009;119:1420-8.
  10. Kong D, Li Y, Wang Z, et al. Cancer Stem Cells and Epithelial-to-Mesenchymal Transition (EMT)-Phenotypic Cells: Are They Cousins or Twins? Cancers (Basel) 2011;3:716-29.
  11. Phua YL, Martel N, Pennisi DJ, et al. Distinct sites of renal fibrosis in Crim1 mutant mice arise from multiple cellular origins. J Pathol 2013;229:685-96.
  12. Garweg JG, Tappeiner C, Halberstadt M. Pathophysiology of proliferative vitreoretinopathy in retinal detachment. Surv Ophthalmol 2013;58:321-9.
  13. Fabian MR, Sonenberg N, Filipowicz W. Regulation of mRNA translation and stability by microRNAs. Annu Rev Biochem 2010;79:351-79.
  14. Wang L, Dong F, Reinach PS, et al. MicroRNA-182 Suppresses HGF/SF-Induced Increases in Retinal Pigment Epithelial Cell Proliferation and Migration through Targeting c-Met. PLoS One 2016;11:e0167684.
  15. Usui-Ouchi A, Ouchi Y, Kiyokawa M, et al. Upregulation of Mir-21 Levels in the Vitreous Humor Is Associated with Development of Proliferative Vitreoretinal Disease. PLoS One 2016;11:e0158043.
  16. Li M, Li H, Liu X, et al. MicroRNA-29b regulates TGF- beta1-mediated epithelial-mesenchymal transition of retinal pigment epithelial cells by targeting AKT2. Exp Cell Res 2016;345:115-24.
  17. Chen X, Ye S, Xiao W, et al. Differentially expressed microRNAs in TGFbeta2-induced epithelial-mesenchymal transition in retinal pigment epithelium cells. Int J Mol Med 2014;33:1195-200.
  18. Adijanto J, Castorino JJ, Wang ZX, et al. Microphthalmia- associated transcription factor (MITF) promotes differentiation of human retinal pigment epithelium (RPE) by regulating microRNAs-204/211 expression. J Biol Chem 2012;287:20491-503.
  19. Jun JH, Joo CK. MicroRNA-124 Controls Transforming Growth Factor beta1-Induced Epithelial-Mesenchymal Transition in the Retinal Pigment Epithelium by Targeting RHOG. Invest Ophthalmol Vis Sci 2016;57:12-22.
  20. Kaneko H, Terasaki H. Biological Involvement of MicroRNAs in Proliferative Vitreoretinopathy. Transl Vis Sci Technol 2017;6:5.
  21. Donato L, Bramanti P, Scimone C, et al. miRNAexpression profile of retinal pigment epithelial cells under oxidative stress conditions. FEBS Open Bio 2018;8:219-33.
  22. Hu B, Xu C, Tian Y, et al. Inflammatory microRNA-194 and -515 attenuate the biosynthesis of chondroitin sulfate during human intervertebral disc degeneration. Oncotarget 2017;8:49303-17.
  23. Morimoto A, Kannari M, Tsuchida Y, et al. An HNF4alpha-microRNA-194/192 signaling axis maintains hepatic cell function. J Biol Chem 2017;292:10574-85.
  24. Yu X, An J, Hua Y, et al. MicroRNA-194 regulates keratinocyte proliferation and differentiation by targeting Grainyhead-like 2 in psoriasis. Pathol Res Pract 2017;213:89-97.
  25. Bao J, Zou JH, Li CY, et al. miR-194 inhibits gastric cancer cell proliferation and tumorigenesis by targeting KDM5B. Eur Rev Med Pharmacol Sci 2016;20:4487-93.
  26. Zhang X, Wei C, Li J, et al. MicroRNA-194 represses glioma cell epithelialtomesenchymal transition by targeting Bmi1. Oncol Rep 2017;37:1593-600.
  27. Li P, Yang Y, Liu H, et al. MiR-194 functions as a tumor suppressor in laryngeal squamous cell carcinoma by targeting Wee1. J Hematol Oncol 2017;10:32.
  28. Das R, Gregory PA, Fernandes RC, et al. MicroRNA-194 Promotes Prostate Cancer Metastasis by Inhibiting SOCS2. Cancer Res 2017;77:1021-34.
  29. Mi J, Zou Y, Lin X, et al. Dysregulation of the miR-194- CUL4B negative feedback loop drives tumorigenesis in non-small-cell lung carcinoma. Mol Oncol 2017;11:305-19.
  30. Zhang Y, Bo Q, Wu W, et al. alpha-Melanocyte- stimulating hormone prevents glutamate excitotoxicity in developing chicken retina via MC4R-mediated down- regulation of microRNA-194. Sci Rep 2015;5:15812.
  31. Vandewalle C, Van Roy F, Berx G. The role of the ZEB family of transcription factors in development and disease. Cell Mol Life Sci 2009;66:773-87.
  32. Kurahara H, Takao S, Maemura K, et al. Epithelial- mesenchymal transition and mesenchymal-epithelial transition via regulation of ZEB-1 and ZEB-2 expression in pancreatic cancer. J Surg Oncol 2012;105:655-61.
  33. Lu L, Neff F, Dun Z, et al. Gene expression profiles derived from single cells in human postmortem brain. Brain Res Brain Res Protoc 2004;13:18-25.
  34. Zheng XZ, Du LF, Wang HP. An immunohistochemical analysis of a rat model of proliferative vitreoretinopathy and a comparison of the expression of TGF-beta and PDGF among the induction methods. Bosn J Basic Med Sci 2010;10:204-9.
  35. Wang J, Zhang J, Chen X, et al. miR-365 promotes diabetic retinopathy through inhibiting Timp3 and increasing oxidative stress. Exp Eye Res 2018;168:89-99.
  36. Donato L, Scimone C, Rinaldi C, et al. Stargardt Phenotype Associated With Two ELOVL4 Promoter Variants and ELOVL4 Downregulation: New Possible Perspective to Etiopathogenesis? Invest Ophthalmol Vis Sci 2018;59:843-57.
  37. Postigo AA. Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. EMBO J 2003;22:2443-52.
  38. Ma L, Young J, Prabhala H, et al. miR-9, a MYC/MYCN- activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol 2010;12:247-56.
  39. Kong W, Yang H, He L, et al. MicroRNA-155 is regulated by the transforming growth factor beta/Smad pathway and contributes to epithelial cell plasticity by targeting RhoA. Mol Cell Biol 2008;28:6773-84.
  40. Sanchez-Tillo E, Lazaro A, Torrent R, et al. ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene 2010;29:3490-500.
  41. Marrs JA, Andersson-Fisone C, Jeong MC, et al. Plasticity in epithelial cell phenotype: modulation by expression of different cadherin cell adhesion molecules. J Cell Biol 1995;129:507-19.
  42. Van Aken EH, De Wever O, Van Hoorde L, et al. Invasion of retinal pigment epithelial cells: N-cadherin, hepatocyte growth factor, and focal adhesion kinase. Invest Ophthalmol Vis Sci 2003;44:463-72.
  43. Antognelli C, Cecchetti R, Riuzzi F, et al. Glyoxalase 1 sustains the metastatic phenotype of prostate cancer cells via EMT control. J Cell Mol Med 2018;22:2865-83.
  44. Donato L, Scimone C, Nicocia G, et al. GLO1 gene polymorphisms and their association with retinitis pigmentosa: a case-control study in a Sicilian population. Mol Biol Rep 2018;45:1349-55. Cite this article as: Cui L, Lyu Y, Jin X, Wang Y, Li X, Wang J, Zhang J, Deng Z, Yang N, Zheng Z, Guo Y, Wang C, Mao R, Xu J, Gao F, Jin C, Zhang J, Tian H, Xu GT, Lu L. miR-194 suppresses epithelial-mesenchymal transition of retinal pigment epithelial cells by directly targeting ZEB1. Ann Transl Med 2019;7(23):751. doi: 10.21037/atm.2019.11.90

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Authors
Cui, L., Lyu, Y., Jin, X., Wang, Y., Li, X., Wang, J., Zhang, J., Deng, Z., Yang, N., Zheng, Z., Guo, Y., Wang, C., Mao, R., Xu, J., Gao, F., Jin, C., Zhang, J., Tian, H., Xu, G.-T., & Lu, L.
Affiliations
  • Tongji University (CN)
  • Shanghai Jiao Tong University (CN)
Corresponding author
  • Tian, Haibin
  • Xu, Guo-Tong
ORCID
Venue
Annals of Translational Medicine
Publisher
AME Publishing Company
Published
2019-12
Volume
7
Issue
23
Pages
751-751
ISSN
  • 2305-5839 (ISSN-L)
  • 2305-5847
DOI
10.21037/atm.2019.11.90
PMC
PMC6990010
OpenAlex
W2996619004
Cited by
35
References
0
Citations by year
2026: 3 · 2025: 1 · 2024: 3 · 2023: 5 · 2022: 2 · 2021: 8 · 2020: 11 · 2019: 1 · 2018: 1
FWCI
1.74
Type
journal article
Language
en
Open access
Licence
cc-by-nc-nd
Locations
  • Annals of Translational Medicine (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › MicroRNA in disease regulation
  • Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Retinal Development and Disorders
Keywords
miR-194, ZEB1, epithelial-mesenchymal transition, retinal pigment epithelial cells, proliferative vitreoretinopathy, TGF-β1, microRNA target regulation, cell migration, phagocytosis, focal adhesions, ARPE-19 cells, retinal gene expression

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