Role of microRNA‑375‑3p‑mediated regulation in tinnitus development

Han,Kyu-Hee; Cho,Hyeeun; Han,Kyeo-Rye; Mun,Seog-Kyun; Kim,Young-Kook; Park,Ilyong; Chang,Munyoung

doi:10.3892/ijmm.2021.4969

Role of microRNA‑375‑3p‑mediated regulation in tinnitus development

Authors:
- Kyu-Hee Han
- Hyeeun Cho
- Kyeo-Rye Han
- Seog-Kyun Mun
- Young-Kook Kim
- Ilyong Park
- Munyoung Chang
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Affiliations: Department of Otorhinolaryngology‑Head and Neck Surgery, National Medical Center, Seoul 04564, Republic of Korea, Department of Otorhinolaryngology‑Head and Neck Surgery, Chung‑Ang University College of Medicine, Seoul 06974, Republic of Korea, Department of Biochemistry, Chonnam National University Medical School, Hwasun, Jeollanam-do 58128, Republic of Korea, Department of Biomedical Engineering, Dankook University College of Medicine, Cheonan, Chungcheongnam-do 16890, Republic of Korea
Published online on: May 21, 2021 https://doi.org/10.3892/ijmm.2021.4969
Article Number: 136
Copyright: © Han et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Changes in the dorsal cochlear nucleus (DCN) following exposure to noise play an important role in the development of tinnitus. As the development of several diseases is known to be associated with microRNAs (miRNAs/miRs), the aim of the present study was to identify the miRNAs that may be implicated in pathogenic changes in the DCN, resulting in tinnitus. A previously developed tinnitus animal model was used for this study. The study consisted of four stages, including identification of candidate miRNAs involved in tinnitus development using miRNA microarray analysis, validation of miRNA expression using reverse transcription‑quantitative PCR (RT‑qPCR), evaluation of the effects of candidate miRNA overexpression on tinnitus development through injection of a candidate miRNA mimic or mimic negative control, and target prediction of candidate miRNAs using mRNA microarray analysis and western blotting. The miRNA microarray and RT‑qPCR analyses revealed that miR‑375‑3p expression was significantly reduced in the tinnitus group compared with that in the non‑tinnitus group. Additionally, miR‑375‑3p overexpression via injection of miR‑375‑3p mimic reduced the proportion of animals with persistent tinnitus. Based on mRNA microarray and western blot analyses, connective tissue growth factor (CTGF) was identified as a potential target for miR‑375‑3p. Thus, it was inferred that CTGF downregulation by miR‑375‑3p may weaken with the decrease in miRNA expression, and the increased pro‑apoptotic activity of CTGF may result in more severe neuronal damage, contributing to tinnitus development. These findings are expected to contribute significantly to the development of a novel therapeutic approach to tinnitus, thereby bringing about a significant breakthrough in the treatment of this potentially debilitating condition.

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1	Axelsson A and Ringdahl A: Tinnitus-a study of its prevalence and characteristics. Br J Audiol. 23:53–62. 1989. View Article : Google Scholar : PubMed/NCBI
2	Hébert S, Canlon B and Hasson D: Emotional exhaustion as a predictor of tinnitus. Psychother Psychosom. 81:324–326. 2012. View Article : Google Scholar : PubMed/NCBI
3	Langguth B: A review of tinnitus symptoms beyond 'ringing in the ears': A call to action. Curr Med Res Opin. 27:1635–1643. 2011. View Article : Google Scholar : PubMed/NCBI
4	Shargorodsky J, Curhan GC and Farwell WR: Prevalence and characteristics of tinnitus among US adults. Am J Med. 123:711–718. 2010. View Article : Google Scholar : PubMed/NCBI
5	Jastreboff PJ: Tinnitus retraining therapy. Prog Brain Res. 166:415–423. 2007. View Article : Google Scholar : PubMed/NCBI
6	Moller AR: Tinnitus: Presence and future. Prog Brain Res. 166:3–16. 2007. View Article : Google Scholar : PubMed/NCBI
7	Cima RFF, Mazurek B, Haider H, Kikidis D, Lapira A, Norena A and Hoare DJ: A multidisciplinary European guideline for tinnitus: Diagnostics, assessment, and treatment. HNO. 67(Suppl 1): S10–S42. 2019. View Article : Google Scholar
8	Tunkel DE, Bauer CA, Sun GH, Rosenfeld RM, Chandrasekhar SS, Cunningham ER Jr, Archer SM, Blakley BW, Carter JM, Granieri EC, et al: Clinical practice guideline: Tinnitus. Otolaryngol Head Neck Surg. 151(Suppl 2): S1–S40. 2014. View Article : Google Scholar : PubMed/NCBI
9	Dehmel S, Pradhan S, Koehler S, Bledsoe S and Shore S: Noise overexposure alters long-term somatosensory-auditory processing in the dorsal cochlear nucleus-possible basis for tinnitus-related hyperactivity? J Neurosci. 32:1660–1671. 2012. View Article : Google Scholar : PubMed/NCBI
10	Koehler SD and Shore SE: Stimulus timing-dependent plasticity in dorsal cochlear nucleus is altered in tinnitus. J Neurosci. 33:19647–19656. 2013. View Article : Google Scholar : PubMed/NCBI
11	Zeng C, Yang Z, Shreve L, Bledsoe S and Shore S: Somatosensory projections to cochlear nucleus are upregulated after unilateral deafness. J Neurosci. 32:15791–15801. 2012. View Article : Google Scholar : PubMed/NCBI
12	Han KH, Mun SK, Sohn S, Piao XY, Park I and Chang M: Axonal sprouting in the dorsal cochlear nucleus affects gap-prepulse inhibition following noise exposure. Int J Mol Med. 44:1473–1483. 2019.PubMed/NCBI
13	Hollins SL and Cairns MJ: MicroRNA: Small RNA mediators of the brains genomic response to environmental stress. Prog Neurobiol. 143:61–81. 2016. View Article : Google Scholar : PubMed/NCBI
14	Campbell K and Booth SA: MicroRNA in neurodegenerative drug discovery: The way forward? Expert Opin Drug Discov. 10:9–16. 2015. View Article : Google Scholar
15	Esteller M: Non-coding RNAs in human disease. Nat Rev Genet. 12:861–874. 2011. View Article : Google Scholar : PubMed/NCBI
16	Gebert LF, Rebhan MA, Crivelli SE, Denzler R, Stoffel M and Hall J: Miravirsen (SPC3649) can inhibit the biogenesis of miR-122. Nucleic Acids Res. 42:609–621. 2014. View Article : Google Scholar
17	National Research Council: Guide for the Care and Use of Laboratory Animals. The National Academies Press Inc; Washington, DC: 2011
18	Paxinos G and Watson C: The Rat Brain in Stereotaxic Coordinates. Academic Press Inc; Burlington, MA: 2006
19	Mun SK, Han KH, Baek JT, Ahn SW, Cho HS and Chang MY: Losartan prevents maladaptive Auditory-Somatosensory plasticity after hearing loss via transforming growth Factor-β signaling suppression. Clin Exp Otorhinolaryngol. 12:33–39. 2019. View Article : Google Scholar
20	Longenecker RJ and Galazyuk AV: Methodological optimization of tinnitus assessment using prepulse inhibition of the acoustic startle reflex. Brain Res. 1485:54–62. 2012. View Article : Google Scholar : PubMed/NCBI
21	Chang MY, Park S, Choi JJ, Kim YK, Suh MW, Lee JH, Oh SH and Park MK: MicroRNAs 218a-5p, 219a-5p, and 221-3p regulate vestibular compensation. Sci Rep. 7:87012017. View Article : Google Scholar : PubMed/NCBI
22	Livak KJ and Schmittgen TD: Analysis of relative gene expressio. data using real-time quantitative PCR and the 2(-Delta Delta C(T)). Method Methods. 25:402–408. 2001. View Article : Google Scholar
23	Ou J, Kou L, Liang L and Tang C: MiR-375 attenuates injury of cerebral ischemia/reperfusion via targetting Ctgf. Biosci Rep. 37:BSR201712422017. View Article : Google Scholar
24	Dugas JC, Cuellar TL, Scholze A, Ason B, Ibrahim A, Emery B, Zamanian JL, Foo LC, McManus MT and Barres BA: Dicer1 and miR-219 Are required for normal oligodendrocyte differentiation and myelination. Neuron. 65:597–611. 2010. View Article : Google Scholar : PubMed/NCBI
25	Giraldez AJ, Cinalli RM, Glasner ME, Enright AJ, Thomson JM, Baskerville S, Hammond SM, Bartel DP and Schier AF: MicroRNAs regulate brain morphogenesis in zebrafish. Science. 308:833–838. 2005. View Article : Google Scholar : PubMed/NCBI
26	Schratt GM, Tuebing F, Nigh EA, Kane CG, Sabatini ME, Kiebler M and Greenberg ME: A brain-specific microRNA regulates dendritic spine development. Nature. 439:283–289. 2006. View Article : Google Scholar : PubMed/NCBI
27	Banerjee-Basu S, Larsen E and Muend S: Common microRNAs target established ASD genes. Front Neurol. 5:2052014. View Article : Google Scholar : PubMed/NCBI
28	Im HI and Kenny PJ: MicroRNAs in neuronal function and dysfunction. Trends Neurosci. 35:325–334. 2012. View Article : Google Scholar : PubMed/NCBI
29	Sun E and Shi Y: MicroRNAs: Small molecules with big roles in neurodevelopment and diseases. Exp Neurol. 268:46–53. 2015. View Article : Google Scholar
30	Ding L, Xu Y, Zhang W, Deng Y, Si M, Du Y, Yao H, Liu X, Ke Y, Si J and Zhou T: MiR-375 frequently downregulated in gastric cancer inhibits cell proliferation by targeting JAK2. Cell Res. 20:784–793. 2010. View Article : Google Scholar : PubMed/NCBI
31	He XX, Chang Y, Meng FY, Wang MY, Xie QH, Tang F, Li PY, Song YH and Lin JS: MicroRNA-375 targets AEG-1 in hepatocellular carcinoma and suppresses liver cancer cell growth in vitro and in vivo. Oncogene. 31:3357–3369. 2012. View Article : Google Scholar
32	Kapsimali M, Kloosterman WP, de Bruijn E, Rosa F, Plasterk RH and Wilson SW: MicroRNAs show a wide diversity of expression profiles in the developing and mature central nervous system. Genome Biol. 8:R1732007. View Article : Google Scholar : PubMed/NCBI
33	Bhinge A, Namboori SC, Bithell A, Soldati C, Buckley NJ and Stanton LW: MiR-375 is essential for human spinal motor neuron development and may be involved in motor neuron degeneration. Stem Cells. 34:124–134. 2016. View Article : Google Scholar
34	Wang C, Pan Y, Cheng B, Chen J and Bai B: Identification of conserved and novel microRNAs in cerebral ischemia-reperfusion injury of rat using deep sequencing. J Mol Neurosci. 54:671–683. 2014. View Article : Google Scholar : PubMed/NCBI
35	Wang Y, Dong X, Li Z, Wang W, Tian J and Chen J: Downregulated RASD1 and upregulated miR-375 are involved in protective effects of calycosin on cerebral ischemia/reperfusion rats. J Neurol Sci. 339:144–148. 2014. View Article : Google Scholar : PubMed/NCBI
36	Hertel M, Tretter Y, Alzheimer C and Werner S: Connective tissue growth factor: A novel player in tissue reorganization after brain injury? Eur J Neurosci. 12:376–380. 2000. View Article : Google Scholar : PubMed/NCBI
37	Hall-Glenn F and Lyons KM: Roles for CCN2 in normal physiological processes. Cell Mol Life Sci. 68:3209–3217. 2011. View Article : Google Scholar : PubMed/NCBI
38	Khodosevich K, Lazarini F, von Engelhardt J, Kaneko H, Lledo PM and Monyer H: Connective tissue growth factor regulates interneuron survival and information processing in the olfactory bulb. Neuron. 79:1136–1151. 2013. View Article : Google Scholar : PubMed/NCBI
39	Bharadwaj HM, Masud S, Mehraei G, Verhulst S and Shinn-Cunningham BG: Individual differences reveal correlates of hidden hearing deficits. J Neurosci. 35:2161–2172. 2015. View Article : Google Scholar : PubMed/NCBI
40	Elgoyhen AB, Langguth B, De Ridder D and Vanneste S: Tinnitus: Perspectives from human neuroimaging. Nat Rev Neurosci. 16:632–642. 2015. View Article : Google Scholar : PubMed/NCBI
41	Becker JB, Prendergast BJ and Liang JW: Female rats are not more variable than male rats: A meta-analysis of neuroscience studies. Biol Sex Differ. 7:342016. View Article : Google Scholar : PubMed/NCBI
42	Itoh Y and Arnold AP: Are females more variable than males in gene expression? Meta-analysis of microarray datasets. Biol Sex Differ. 6:182015. View Article : Google Scholar : PubMed/NCBI
43	Lauer AM and Schrode KM: Sex bias in basic and preclinical noise-induced hearing loss research. Noise Health. 19:207–212. 2017. View Article : Google Scholar : PubMed/NCBI