MicroRNA expression profiling in tears and blood as predictive biomarkers for anti-VEGF treatment response in wet age-related macular degeneration

Chu-Yu Yen1, Chi-Ming Chiu2, I-Mo Fang3,4,5,6
1Department of Ophthalmology, Taipei City Hospital, Ren-Ai Branch, Taipei, Taiwan
2Department of Biotechnology, Ming Chuan University, Taoyuan City, Taiwan
3Department of Optometry, MacKay Medical College, New Taipei City, Taiwan
4Department of Ophthalmology, Taipei City Hospital Zhongxiao Branch, Taipei, Taiwan
5Department of Special Education, University of Taipei, Taipei, Taiwan
6Department of Ophthalmology, National Taiwan University Hospital, Taipei,Taiwan

Tóm tắt

This study aimed to investigate the potential of microRNAs (miRNAs) in tears, blood, and aqueous humor as biomarkers for predicting treatment response in wet age-related macular degeneration (AMD) patients undergoing anti-vascular endothelial growth factor (anti-VEGF) therapy. In a single-center prospective cohort study, treatment-naïve wet AMD patients and age-matched controls were enrolled. Clinical data and miRNA levels (miR-199a-3p, miR-365-3p, miR-200b-3p, miR-195-5p, miR-335-5p, and miR-185-5p) in tears, blood, and aqueous humor were collected. Treatment response was categorized into responders and non-responders based on visual acuity and central subfield thickness. MiRNA levels were quantified using reverse-transcription PCR. Statistical analyses were performed, including ROC analysis, to evaluate predictive accuracy. Dysregulated miRNA profiles were observed in wet AMD tears and blood compared to controls. Specifically, miR-199a-3p, miR-195-5p, and miR-185-5p were upregulated, while miR-200b-3p was downregulated in tears. All six miRNAs were elevated in wet AMD blood samples. Notably, responders showed higher tear expression of miR-195-5p and miR-185-5p. Combining these miRNAs yielded the highest predictive power (AUC = 0.878, p = 0.006) for anti-VEGF responders. Dysregulated miRNA profiles in tears and blood suggest their potential as biomarkers for wet AMD. MiR-195-5p and miR-185-5p in tears demonstrate predictive value for anti-VEGF treatment responders. This study underscores the non-invasive prediction potential of miRNA tear analysis in wet AMD treatment responses.

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Tài liệu tham khảo

Li JQ, Welchowski T, Schmid M et al (2020) Prevalence and incidence of age-related macular degeneration in Europe: a systematic review and meta-analysis. Br J Ophthalmol 104(8):1077–1084. https://doi.org/10.1136/bjophthalmol-2019-314422 Colijn JM, Buitendijk GHS, Prokofyeva E et al (2017) Prevalence of age-related macular degeneration in Europe: the past and the future. Ophthalmology 124(12):1753–1763. https://doi.org/10.1016/j.ophtha.2017.05.035 Veritti D, Sarao V, Lanzetta P (2012) Neovascular age-related macular degeneration. Ophthalmologica 227(Suppl 1):11–20. https://doi.org/10.1159/000337154 Saxena N, George PP, Hoon HB et al (2016) The burden of wet age-related macular degeneration and its economic implications in singapore in the Year 2030. Ophthalmic Epidemiol 23(4):232–237. https://doi.org/10.1080/09286586.2016.1193617 Solomon SD, Lindsley K, Vedula SS et al (2014) Anti-vascular endothelial growth factor for neovascular age-related macular degeneration. Cochrane Database Syst Rev. 8(8):CD005139. https://doi.org/10.1002/14651858 CATT Research Group, Martin DF, Maguire MG, Ying GS et al (2011) Ranibizumab and bevacizumab for neovascular age-related macular degeneration. N Engl J Med. 364(20):1897–908. https://doi.org/10.1056/NEJMoa1102673 Comparison of Age-related Macular Degeneration Treatments Trials (CATT) Research Group, Martin DF, Maguire MG, Fine SL et al (2012) Ranibizumab and bevacizumab for treatment of neovascular age-related macular degeneration: two-year results. Ophthalmology. 119(7):1388–98. https://doi.org/10.1016/j.ophtha.2012.03.053 Mettu PS, Allingham MJ, Cousins SW (2021) Incomplete response to Anti-VEGF therapy in neovascular AMD: Exploring disease mechanisms and therapeutic opportunities. Prog Retin Eye Res 82:100906. https://doi.org/10.1016/j.preteyeres.2020.100906 Amoaku WM, Chakravarthy U, Gale R et al (2015) Defining response to anti-VEGF therapies in neovascular AMD. Eye (Lond) 29(6):721–731. https://doi.org/10.1038/eye.2015.48 Barış ME, Menteş J, Afrashi F et al (2020) Subgroups and features of poor responders to anti-vascular endothelial growth factor treatment in eyes with neovascular age-related macular degeneration. Turk J Ophthalmol 50(5):275–282. https://doi.org/10.4274/tjo.galenos.2020.38488 Saliminejad K, Khorram Khorshid HR, Soleymani Fard S et al (2019) An overview of microRNAs: Biology, functions, therapeutics, and analysis methods. J Cell Physiol 234(5):5451–5465. https://doi.org/10.1002/jcp.27486 Hyttinen JMT, Blasiak J, Felszeghy S et al (2021) MicroRNAs in the regulation of autophagy and their possible use in age-related macular degeneration therapy. Ageing Res Rev 67:101260. https://doi.org/10.1016/j.arr.2021.101260 Romano GL, Platania CBM, Drago F et al (2017) Retinal and circulating miRNAs in age-related macular degeneration: An In vivo Animal and human study. Front Pharmacol 8:168. https://doi.org/10.3389/fphar.2017.00168 Chu-Tan JA, Rutar M, Saxena K et al (2018) MicroRNA-124 dysregulation is associated with retinal inflammation and photoreceptor death in the degenerating retina. Invest Ophthalmol Vis Sci 59(10):4094–4105. https://doi.org/10.1167/iovs.18-24623 Blasiak J, Watala C, Tuuminen R et al (2019) Expression of VEGFA-regulating miRNAs and mortality in wet AMD. J Cell Mol Med 23(12):8464–8471. https://doi.org/10.1111/jcmm.14731 Sun L, Liu X, Zuo Z (2021) Regulatory role of miRNA-23a in diabetic retinopathy. Exp Ther Med 22(6):1477. https://doi.org/10.3892/etm.2021.10912 Kim YJ, Yeon Y, Lee WJ et al (2019) Comparison of MicroRNA expression in tears of normal subjects and Sjögren syndrome patients. Invest Ophthalmol Vis Sci 60(14):4889–4895. https://doi.org/10.1167/iovs.19-27062 Raga-Cervera J, Bolarin JM, Millan JM et al (2021) miRNAs and Genes Involved in the Interplay between ocular hypertension and primary open-angle glaucoma oxidative stress, inflammation, and apoptosis networks. J Clin Med. 10(11):2227. https://doi.org/10.3390/jcm10112227 Wang Q, Xie X, Li H et al (2020) Discovery of microRNA expression profiles involved in regulating TGF-β2 expression in the tears of dry eye patients. Ann Clin Biochem 57(6):420–428. https://doi.org/10.1177/0004563220961746 Kim YJ, Yeon Y, Lee WJ et al (2022) Analysis of MicroRNA expression in tears of patients with herpes epithelial keratitis: a preliminary study. Invest Ophthalmol Vis Sci 63(4):21. https://doi.org/10.1167/iovs.63.4.21 Syed NH, Shahidan WNS, Shatriah I et al (2022) MicroRNA profiling of the tears of children with vernal keratoconjunctivitis. Front Genet 13:847168. https://doi.org/10.3389/fgene.2022.847168 Grieco GE, Sebastiani G, Eandi CM et al (2020) MicroRNA expression in the aqueous humor of patients with diabetic macular Edema. Int J Mol Sci 21(19):7328. https://doi.org/10.3390/ijms21197328 Zheng K, Wang N, Shen Y et al (2018) Pro-apoptotic effects of micro-ribonucleic acid-365 on retinal neurons by targeting insulin-like growth factor-1 in diabetic rats: An in vivo and in vitro study. J Diabetes Investig 9(5):1041–1051. https://doi.org/10.1111/jdi.12815 Wang J, Zhang J, Chen X et al (2018) miR-365 promotes diabetic retinopathy through inhibiting Timp3 and increasing oxidative stress. Exp Eye Res 168:89–99. https://doi.org/10.1016/j.exer.2017.11.006 Wang H, Wang Z, Tang Q (2018) Reduced expression of microRNA-199a-3p is associated with vascular endothelial cell injury induced by type 2 diabetes mellitus. Exp Ther Med 16(4):3639–3645. https://doi.org/10.3892/etm.2018.6655 Ren C, Liu Q, Wei Q et al (2017) Circulating miRNAs as potential biomarkers of age-related macular degeneration. Cell Physiol Biochem 41(4):1413–1423. https://doi.org/10.1159/000467941 Wu J, Chen J, Hu J et al (2023) CircRNA Uxs1/miR-335-5p/PGF axis regulates choroidal neovascularization via the mTOR/p70 S6k pathway. Transl Res 256:41–55. https://doi.org/10.1016/j.trsl.2023.01.003 Friedrich J, Steel DHW, Schlingemann RO et al (2023) microRNA expression profile in the vitreous of proliferative diabetic retinopathy patients and differences from patients treated with Anti-VEGF therapy. Transl Vis Sci Technol 9(6):16. https://doi.org/10.1167/tvst.9.6.16 Cho H, Hwang M, Hong EH et al (2020) Micro-RNAs in the aqueous humour of patients with diabetic macular oedema. Clin Exp Ophthalmol 48(5):624–635. https://doi.org/10.1111/ceo.13750 Natoli R, Fernando N (2018) MicroRNA as therapeutics for age-related macular degeneration. Adv Exp Med Biol 1074:37–43. https://doi.org/10.1007/978-3-319-75402-4_5 Urbańska K, Stępień PW, Nowakowska KN et al (2022) The role of dysregulated miRNAs in the pathogenesis, diagnosis and treatment of age-related macular degeneration. Int J Mol Sci 23(14):7761. https://doi.org/10.3390/ijms23147761 Weber JA, Baxter DH, Zhang S et al (2010) The microRNA spectrum in 12 body fluids. Clin Chem 56(11):1733–1741. https://doi.org/10.1373/clinchem.2010.147405 Hindle AG, Thoonen R, Jasien JV et al (2019) Identification of candidate miRNA biomarkers for glaucoma. Invest Ophthalmol Vis Sci 60(1):134–146. https://doi.org/10.1167/iovs.18-24878 Bates DO (2010) Vascular endothelial growth factors and vascular permeability. Cardiovasc Res 87(2):262–271. https://doi.org/10.1093/cvr/cvq105 Ishikawa K, Kannan R, Hinton DR (2016) Molecular mechanisms of subretinal fibrosis in age-related macular degeneration. Exp Eye Res 142:19–25. https://doi.org/10.1016/j.exer.2015.03.009 Sato T, Takeuchi M, Karasawa Y et al (2018) Intraocular inflammatory cytokines in patients with neovascular age-related macular degeneration before and after initiation of intravitreal injection of anti-VEGF inhibitor. Sci Rep 8(1):1098. https://doi.org/10.1038/s41598-018-19594-6 Damico FM, Gasparin F, Scolari MR et al (2012) New approaches and potential treatments for dry age-related macular degeneration. Arq Bras Oftalmol 75(1):71–76. https://doi.org/10.1590/s0004-27492012000100016 Armstrong DA, Green BB, Seigne JD et al (2015) MicroRNA molecular profiling from matched tumor and bio-fluids in bladder cancer. Mol Cancer 14:194. https://doi.org/10.1186/s12943-015-0466-2 Zhang Y, Zhang D, Wang F et al (2015) Serum miRNAs panel (miR-16-2*, miR-195, miR-2861, miR-497) as novel non-invasive biomarkers for detection of cervical cancer. Sci Rep 5:17942. https://doi.org/10.1038/srep17942 Jin Y, Wang M, Hu H et al (2018) Overcoming stemness and chemoresistance in colorectal cancer through miR-195-5p-modulated inhibition of notch signaling. Int J Biol Macromol 117:445–453 Wu J, Ji A, Wang X et al (2015) MicroRNA-195-5p, a new regulator of Fra-1, suppresses the migration and invasion of prostate cancer cells. J Transl Med 13:289 Dai J, Wei R, Zhang P (2022) Retraction Note: Overexpression of microRNA-195-5p reduces cisplatin resistance and angiogenesis in ovarian cancer by inhibiting the PSAT1-dependent GSK3β/β-catenin signaling pathway. J Transl Med 20(1):351. https://doi.org/10.1186/s12967-022-03560-y Wang R, Zhao N, Li S et al (2013) MicroRNA-195 suppresses angiogenesis and metastasis of hepatocellular carcinoma by inhibiting the expression of VEGF, VAV2, and CDC42. Hepatology 58:642–653 Ma X, Liu H, Zhu J et al (2022) miR-185-5p regulates inflammation and phagocytosis through CDC42/JNK pathway in macrophages. Genes (Basel) 13(3):468. https://doi.org/10.3390/genes13030468 Tian J, Cheng L, Kong E et al (2022) linc00958/miR-185-5p/RSF-1 modulates cisplatin resistance and angiogenesis through AKT1/GSK3β/VEGFA pathway in cervical cancer. Reprod Biol Endocrinol 20(1):132. https://doi.org/10.1186/s12958-022-00995-2