Abnormal expression of miR‑135a in patients with depression and its possible involvement in the pathogenesis of the condition

Ding,Yinxia; Zhong,Ming; Qiu,Bingjie; Liu,Chuanpeng; Wang,Jinfeng; Liang,Jie

doi:10.3892/etm.2021.10158

Abnormal expression of miR‑135a in patients with depression and its possible involvement in the pathogenesis of the condition

Authors:
- Yinxia Ding
- Ming Zhong
- Bingjie Qiu
- Chuanpeng Liu
- Jinfeng Wang
- Jie Liang
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Affiliations: Department of Psychiatry, Binzhou Youfu Hospital, Binzhou, Shandong 256600, P.R. China, Department of Psychiatry, Binzhou People's Hospital, Binzhou, Shandong 256600, P.R. China, Binzhou Family Planning Association, Binzhou, Shandong 256600, P.R. China, Ministry of Public Infrastructure, Zhaoqing Medical College, Zhaoqing, Guangdong 526020, P.R. China
Published online on: May 4, 2021 https://doi.org/10.3892/etm.2021.10158
Article Number: 726
Copyright: © Ding et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

At present, due to the increasing pressures on society and the stress of everyday living, the number of individuals suffering from depression has increased. Therefore, the treatment of depression has also received increasing attention. MicroRNA (miRNA/miR)‑135a is a well‑studied miRNA. It has been reported that miR‑135a is significantly downregulated in patients with depression and may be a potential marker for the diagnosis of the condition. However, the specific mechanisms of action of miR‑135a in patients with depression remain unclear. In the present study, it was found that miR‑135a was downregulated in patients with depression, and in a mouse model of depression. The effects of miR‑135a on depression‑related symptoms in mice were then explored. In the mice with chronic unpredictable mild stress (CUMS) that were treated with miR‑135a for 3 weeks, a significantly reduced level of weight gain was observed in comparison with the control group. In addition, treatment with miR‑135a mimic significantly increased sucrose preference in the sucrose preference test in the mice, and reduced the immobility time in the forced swimming test and tail suspension test. Treatment with miR‑135a mimic also inhibited CUMS‑induced hippocampal cell apoptosis. Furthermore, treatment with miR‑135a mimic and fluoxetine significantly reduced the CUMS‑induced increase in the expression levels of inflammatory factors (IL‑1β, IL‑6 and TNF‑α) in the hippocampus of the mice. Subsequently, reverse transcription‑quantitative polymerase chain reaction and western blot analysis revealed that treatment with miR‑135a mimic significantly inhibited the expression of Toll‑like receptor 4 in the mouse hippocampus. In conclusion, the findings of the present study indicate that miR‑135a may be a novel potential target for the treatment of depression.

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1	Bortolato B, Carvalho AF, Soczynska JK, Perini GI and McIntyre RS: The involvement of TNF-α in cognitive dysfunction associated with major depressive disorder: An opportunity for domain specific treatments. Curr Neuropharmacol. 13:558–576. 2015.PubMed/NCBI View Article : Google Scholar
2	Belmaker RH and Agam G: Major depressive disorder. N Engl J Med. 358:55–68. 2008.PubMed/NCBI View Article : Google Scholar
3	Prokofieva M, Koukia E and Dikeos D: Mental health nursing in Greece: Nursing diagnoses and interventions in major depression. Issues Ment Health Nurs. 37:556–562. 2016.PubMed/NCBI View Article : Google Scholar
4	Chuang YH and Kuo LM: Nurses' confidence in providing and managing care for older persons with depressive symptoms or depression in long-term care facilities: A national survey. Int J Ment Health Nurs. 27:1767–1775. 2018.PubMed/NCBI View Article : Google Scholar
5	Xie X, Shi Y and Zhang J: Structural network connectivity impairment and depressive symptoms in cerebral small vessel disease. J Affect Disord. 220:8–14. 2017.PubMed/NCBI View Article : Google Scholar
6	Suzuki H, Matsumoto Y, Ota H, Sugimura K, Takahashi J, Ito K, Miyata S, Furukawa K, Arai H, Fukumoto Y, et al: Hippocampal blood flow abnormality associated with depressive symptoms and cognitive impairment in patients with chronic heart failure. Circ J. 80:1773–1780. 2016.PubMed/NCBI View Article : Google Scholar
7	Nabavi SM, Daglia M, Braidy N and Nabavi SF: Natural products, micronutrients, and nutraceuticals for the treatment of depression: A short review. Nutr Neurosci. 20:180–194. 2017.PubMed/NCBI View Article : Google Scholar
8	Weil-Malherbe H: The biochemistry of affective disorders. In: Handbook of Neurochemistry. Springer, Boston, MA, pp371-416, 1972.
9	Lee S, Jeong J, Kwak Y and Park SK: Depression research: Where are we now? Mol Brain. 3:8–0. 2010.PubMed/NCBI View Article : Google Scholar
10	Ebmeier KP, Donaghey C and Steele JD: Recent developments and current controversies in depression. Lancet. 367:153–167. 2006.PubMed/NCBI View Article : Google Scholar
11	Leistedt SJ and Linkowski P: Brain, networks, depression, and more. Eur Neuropsychopharmacol. 23:55–62. 2013.PubMed/NCBI View Article : Google Scholar
12	Kessler RC: The costs of depression. Psychiatr Clin North Am. 35:1–14. 2012.PubMed/NCBI View Article : Google Scholar
13	Ota KT and Duman RS: Environmental and pharmacological modulations of cellular plasticity: Role in the pathophysiology and treatment of depression. Neurobiol Dis. 57:28–37. 2013.PubMed/NCBI View Article : Google Scholar
14	Bartel DP: MicroRNAs: Genomics, biogenesis, mechanism, and function. Cell. 116:281–297. 2004.PubMed/NCBI View Article : Google Scholar
15	Calin GA, Sevignani C, Dumitru CD, Hyslop T, Noch E, Yendamuri S, Shimizu M, Rattan S, Bullrich F, Negrini M, et al: Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers. Proc Natl Acad Sci USA. 101:2999–3004. 2004.PubMed/NCBI View Article : Google Scholar
16	Krol J, Loedige I and Filipowicz W: The widespread regulation of microRNA biogenesis, function and decay. Nat Rev Genet. 11:597–610. 2010.PubMed/NCBI View Article : Google Scholar
17	Mendell J and Olson E: . MicroRNAs in stress signaling and human disease. Cell. 148:1172–1187. 2012.PubMed/NCBI View Article : Google Scholar
18	Maes OC, Chertkow HM, Wang E and Schipper HM: MicroRNA: Implications for Alzheimer disease and other human CNS disorders. Curr Genomics. 10:154–168. 2009.PubMed/NCBI View Article : Google Scholar
19	Kocerha J, Kauppinen S and Wahlestedt C: MicroRNAs in CNS disorders. Neuromolecular Med. 11:162–172. 2009.PubMed/NCBI View Article : Google Scholar
20	Zeng YB, Liang XH, Zhang GX, Jiang N, Zhang T, Huang JY, Zhang L and Zeng XC: miRNA-135a promotes hepatocellular carcinoma cell migration and invasion by targeting forkhead box O1. Cancer Cell Int. 16(63)2016.PubMed/NCBI View Article : Google Scholar
21	Yao S, Tian C, Ding Y, Ye Q, Gao Y, Yang N and Li Q: Down-regulation of Krüppel-like factor-4 by microRNA-135a-5p promotes proliferation and metastasis in hepatocellular carcinoma by transforming growth factor-β1. Oncotarget. 7:42566–42578. 2016.PubMed/NCBI View Article : Google Scholar
22	Ren JW, Li ZJ and Tu C: miR-135 post-transcriptionally regulates FOXO1 expression and promotes cell proliferation in human malignant melanoma cells. Int J Clin Exp Pathol. 8:6356–6366. 2015.PubMed/NCBI
23	Xu B, Lu X, Zhao Y, Liu C, Huang X, Chen S, Zhu W, Zhang L and Chen M: MicroRNA-135a induces prostate cancer cell apoptosis via inhibition of STAT6. Oncol Lett. 17:1889–1895. 2019.PubMed/NCBI View Article : Google Scholar
24	Gheysarzadeh A, Sadeghifard N, Afraidooni L, Pooyan F, Mofid MR, Valadbeigi H, Bakhtiari H and Keikhavani S: Serum-based microRNA biomarkers for major depression: miR-16, miR-135a, and miR-1202. J Res Med Sci. 23(69)2018.PubMed/NCBI View Article : Google Scholar
25	Deng XY, Li HY, Chen JJ, Li RP, Qu R, Fu Q and Ma SP: Thymol produces an antidepressant-like effect in a chronic unpredictable mild stress model of depression in mice. Behav Brain Res. 291:12–19. 2015.PubMed/NCBI View Article : Google Scholar
26	Chen YP, Wang C and Xu JP: Chronic unpredictable mild stress induced depression-like behaviours and glutamate-glutamine cycling dysfunctions in both blood and brain of mice. Pharm Biol. 57:280–286. 2019.PubMed/NCBI View Article : Google Scholar
27	Duan CM, Zhang JR, Wan TF, Wang Y, Chen HS and Liu L: SRT2104 attenuates chronic unpredictable mild stress-induced depressive-like behaviors and imbalance between microglial M1 and M2 phenotypes in the mice. Behav Brain Res. 378(112296)2020.PubMed/NCBI View Article : Google Scholar
28	Lian N, Niu Q, Lei Y, Li X, Li Y and Song X: miR-221 is involved in depression by regulating Wnt2/CREB/BDNF axis in hippocampal neurons. Cell Cycle. 17:2745–2755. 2018.PubMed/NCBI View Article : Google Scholar
29	Iñiguez SD, Riggs LM, Nieto SJ, Dayrit G, Zamora NN, Shawhan KL, Cruz B and Warren BL: Social defeat stress induces a depression-like phenotype in adolescent male c57BL/6 mice. Stress. 17:247–255. 2014.PubMed/NCBI View Article : Google Scholar
30	Steru L, Chermat R, Thierry B and Simon P: The tail suspension test: A new method for screening antidepressants in mice. Psychopharmacology (Berl). 85:367–370. 1985.PubMed/NCBI View Article : Google Scholar
31	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
32	Xie B, Lu C, Chen C, Zhou J and Deng Z: miR-135a alleviates silica-induced pulmonary fibrosis by targeting NF-κB/Inflammatory signaling pathway. Mediators Inflamm. 2020(1231243)2020.PubMed/NCBI View Article : Google Scholar
33	Ferrúa CP, Giorgi R, da Rosa LC, do Amaral CC, Ghisleni GC, Pinheiro RT and Nedel F: MicroRNAs expressed in depression and their associated pathways: A systematic review and a bioinformatics analysis. J Chem Neuroanat. 100(101650)2019.PubMed/NCBI View Article : Google Scholar
34	Allen L and Dwivedi Y: MicroRNA mediators of early life stress vulnerability to depression and suicidal behavior. Mol Psychiatry. 25:308–320. 2020.PubMed/NCBI View Article : Google Scholar
35	Lou D, Wang J and Wang X: miR-124 ameliorates depressive-like behavior by targeting STAT3 to regulate microglial activation. Mol Cell Probes. 48(101470)2019.PubMed/NCBI View Article : Google Scholar
36	Xu B, Tao T, Wang Y, Fang F, Huang Y, Chen S, Zhu W and Chen M: hsa-miR-135a-1 inhibits prostate cancer cell growth and migration by targeting EGFR. Tumour Biol. 37:14141–14151. 2016.PubMed/NCBI View Article : Google Scholar
37	Shi H, Ji Y, Zhang D, Liu Y and Fang P: miR-135a inhibits migration and invasion and regulates EMT-related marker genes by targeting KLF8 in lung cancer cells. Biochem Biophys Res Commun. 465:125–130. 2015.PubMed/NCBI View Article : Google Scholar
38	Yan LH, Chen ZN, Li-Li Chen J, Wei WE, Mo XW, Qin YZ, Lin Y and Chen JS: miR-135a promotes gastric cancer progression and resistance to oxaliplatin. Oncotarget. 7:70699–70714. 2016.PubMed/NCBI View Article : Google Scholar
39	Zhou W, Li X, Liu F, Xiao Z, He M, Shen S and Liu S: miR-135a promotes growth and invasion of colorectal cancer via metastasis suppressor 1 in vitro. Acta Biochim Biophys Sin (Shanghai). 44:838–846. 2012.PubMed/NCBI View Article : Google Scholar
40	Shi HZ, Wang DN, Xu F, Teng JH and Wang YL: miR-135a inhibits glioma cell proliferation and invasion by directly targeting FOXO1. Eur Rev Med Pharmacol Sci. 22:4215–4223. 2018.PubMed/NCBI View Article : Google Scholar
41	Henn FA and Vollmayr B: Stress models of depression: Forming genetically vulnerable strains. Neurosci Biobehav Rev. 29:799–804. 2005.PubMed/NCBI View Article : Google Scholar
42	Wan YQ, Feng JG, Li M, Wang MZ, Liu L, Liu X, Duan XX, Zhang CX and Wang XB: Prefrontal cortex miR-29b-3p plays a key role in the antidepressant-like effect of ketamine in rats. Exp Mol Med. 50:1–14. 2018.PubMed/NCBI View Article : Google Scholar
43	Dey A and Hankey Giblin PA: Insights into macrophage heterogeneity and cytokineinduced neuroinflammation in major depressive disorder. Pharmaceuticals (Basel). 11(E64)2018.PubMed/NCBI View Article : Google Scholar
44	Iwata M, Ota KT and Duman RS: The inflammasome: Pathways linking psychological stress, depression, and systemic illnesses. Brain Behav Immun. 31:105–114. 2013.PubMed/NCBI View Article : Google Scholar
45	Rush G, O'Donovan A, Nagle L, Conway C, McCrohan A, O'Farrelly C, Lucey JV and Malone KM: Alteration of immune markers in a group of melancholic depressed patients and their response to electroconvulsive therapy. J Affect Disord. 205:60–68. 2016.PubMed/NCBI View Article : Google Scholar
46	Shen Z, Xu Y, Jiang X, Wang Z, Guo Y, Pan W and Hou J: Avicularin relieves depressive-like behaviors induced by chronic unpredictable mild stress in mice. Med Sci Monit. 24:1643–3750. 2018.PubMed/NCBI View Article : Google Scholar
47	Du XJ and Lu JM: miR-135a represses oxidative stress and vascular inflammatory events via targeting toll-like receptor 4 in atherogenesis. J Cell Biochem. 119:6154–6161. 2018.PubMed/NCBI View Article : Google Scholar
48	den Dekker WK, Cheng C, Pasterkamp G and Duckers HJ: Toll like receptor 4 in atherosclerosis and plaque destabilization. Atherosclerosis. 209:314–320. 2010.PubMed/NCBI View Article : Google Scholar
49	Yang L and Gao C: miR-590 inhibits endothelial cell apoptosis by inactivating the TLR4/NF-κB pathway in atherosclerosis. Yonsei Med J. 60:298–307. 2019.PubMed/NCBI View Article : Google Scholar