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miR-146a down-regulation alleviates H2O2-induced cytotoxicity of PC12 cells by regulating MCL1/JAK/STAT pathway

miR-146a down-regulation relieves H2O2-induced PC12 cells cytotoxicity by MCL1/JAK/STAT

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Abstract

Oxidative stress and miRNAs have been confirmed to play an important role in neurological diseases. The study aimed to explore the underlying effect and mechanisms of miR-146a in H2O2-induced injury of PC12 cells. Here, PC12 cells were stimulated with 200 μM of H2O2 to construct oxidative injury model. Cell injury was evaluated on the basis of the changes in cell viability, migration, invasion, apoptosis, and DNA damage. Results revealed that miR-146a expression was up-regulated in H2O2-induced PC12 cells. Functional analysis showed that down-regulation of miR-146a alleviated H2O2-induced cytotoxicity in PC12 cells. Dual-luciferase reporter and western blot assay verified that MCL1 was a direct target gene of miR-146a. Moreover, anti-miR-146a-mediated suppression on cell cytotoxicity was abated following MCL1 knockdown in H2O2-induced PC12 cells. Furthermore, MCL1 activated JAK/STAT signaling pathway and MCL1 overexpression attenuated H2O2-induced cytotoxicity in PC12 cells by JAK/STAT signaling pathway. In conclusion, this study suggested that suppression of miR-146a abated H2O2-induced cytotoxicity in PC12 cells via regulating MCL1/JAK/STAT pathway.

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Abbreviations

AD:

Alzheimer’s disease

ATCC:

American Tissue Culture Collection

CCK-8:

Cell Counting Kit-8

CIS:

Chemotherapy-induced senescence

H2O2 :

Hydrogen peroxide

MCL1:

Myeloid cell leukemia 1

MCL1-WT:

Wild-type MCL1 report vector

MCL1-MUT:

Mutant-type MCL1 report vector

miRNAs:

MicroRNAs

ROS:

Reactive oxygen species

References

  • Arena A, Iyer AM, Milenkovic I, Kovács GG, Ferrer I, Perluigi M, et al. Developmental expression and dysregulation of miR-146a and miR-155 in Down's syndrome and mouse models of Down’s syndrome and Alzheimer's disease. Curr Alzheimer Res. 2017;14:1305–17.

    Article  CAS  PubMed  Google Scholar 

  • Aronica E, Fluiter K, Iyer A, Zurolo E, Vreijling J, Van Vliet E, et al. Expression pattern of miR-146a, an inflammation-associated microRNA, in experimental and human temporal lobe epilepsy. Eur J Neurosci. 2010;31:1100–7.

    Article  CAS  PubMed  Google Scholar 

  • Calin GA, Croce CM. Chromosomal rearrangements and microRNAs: a new cancer link with clinical implications. J Clin Invest. 2007;117:2059–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cao DD, Li L, Chan WY. MicroRNAs: key regulators in the central nervous system and their implication in neurological diseases. Int J Mol Sci. 2016;17:E842.

    Article  CAS  PubMed  Google Scholar 

  • Carvalho AN, Firuzi O, Gama MJ, Van HJ, Saso L. Oxidative stress and antioxidants in neurological diseases: is there still hope? Curr Drug Targets. 2016;18:705–18.

    Article  CAS  Google Scholar 

  • Chen L, Sun L, Liu Z, Wang H, Xu C. Protection afforded by quercetin against H2O2-induced apoptosis on PC12 cells via activating PI3K/Akt signal pathway. J Recept Signal Transduct Res. 2016;36:98–102.

    Article  CAS  PubMed  Google Scholar 

  • Cheng B, Lu H, Bai B, Chen J. d-β-Hydroxybutyrate inhibited the apoptosis of PC12 cells induced by H2O2 via inhibiting oxidative stress. Neurochem Int. 2013;62:620–5.

    Article  CAS  PubMed  Google Scholar 

  • Coskun M, Salem M, Pedersen J, Nielsen OH. Involvement of JAK/STAT signaling in the pathogenesis of inflammatory bowel disease. Pharmacol Res. 2013;76:1–8.

    Article  CAS  Google Scholar 

  • Cui JG, Li YY, Zhao Y, Bhattacharjee S, Lukiw WJ. Differential regulation of interleukin-1 receptor-associated kinase-1 (IRAK-1) and IRAK-2 by microRNA-146a and NF-κB in stressed human astroglial cells and in Alzheimer disease. J Biol Chem. 2010;285:38951–60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Demelash A, Pfannenstiel LW, Liu L, Gastman BR. Mcl-1 regulates reactive oxygen species via NOX4 during chemotherapy-induced senescence. Oncotarget. 2017;8:28154–68.

    Article  PubMed  PubMed Central  Google Scholar 

  • Guo Y, Niu S. MiR-25 protects PC-12 cells from H2O2 mediated oxidative damage via WNT/β-catenin pathway. J Spinal Cord Med. 2017;12:1–10.

    Google Scholar 

  • Haenisch S, von Rüden EL, Wahmkow H, Rettenbeck ML, Michler C, Russmann V, et al. miRNA-187-3p-mediated regulation of the KCNK10/TREK-2 potassium channel in a rat epilepsy model. ACS Chem Neurosci. 2016;7:1585–94.

    Article  CAS  PubMed  Google Scholar 

  • Ji G, Lv K, Chen H, Wang T, Wang Y, Zhao D, et al. MiR-146a regulates SOD2 expression in H2O2 stimulated PC12 cells. PLoS One. 2013;8:e69351.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jiang R, Zhang C, Zhang Z, Liu G, Gu R, Wu H. Knockdown of miR-125-3p protects against oxidative stress in PC-12 cells by targeting MEF2. Int J Clin Exp Pathol. 2017;10:5171–9.

    CAS  Google Scholar 

  • Kamat PK, Kalani A, Rai S, Swarnkar S, Tota S, Nath C, et al. Mechanism of oxidative stress and synapse dysfunction in the pathogenesis of Alzheimer’s disease: understanding the therapeutics strategies. Mol Neurobiol. 2016;53:648–61.

    Article  CAS  PubMed  Google Scholar 

  • Kotschy A, Szlavik Z, Murray J, Davidson J, Maragno AL, Le Toumelin-Braizat G, et al. The MCL1 inhibitor S63845 is tolerable and effective in diverse cancer models. Nature. 2016;538:477–82.

    Article  CAS  PubMed  Google Scholar 

  • La Fortezza M, Schenk M, Cosolo A, Kolybaba A, Grass I, Classen AK. JAK/STAT signalling mediates cell survival in response to tissue stress. Development. 2016;143:2907–19.

    Article  CAS  PubMed  Google Scholar 

  • Li P, Shen M, Gao F, Wu J, Zhang J, Teng F, et al. An antagomir to microRNA-106b-5p ameliorates cerebral ischemia and reperfusion injury in rats via inhibiting apoptosis and oxidative stress. Mol Neurobiol. 2016;54:2901–21.

    Article  CAS  PubMed  Google Scholar 

  • Li R, Yin F, Guo Y, Zhao K, Ruan Q, Qi Y. Long non-coding RNA H19 protects PC-12 cells from hydrogen peroxide-induced injury by targeting miR-155 in spinal cord injury. Int J Clin Exp Pathol. 2017a;10:6210–23.

    Google Scholar 

  • Li R, Yin F, Guo YY, Zhao KC, Ruan Q, Qi YM. Knockdown of ANRIL aggravates H2O2-induced injury in PC-12 cells by targeting microRNA-125a. Biomed Pharmacother. 2017b;92:952–61.

    Article  CAS  PubMed  Google Scholar 

  • Lin P, Tian XH, Yi YS, Jiang WS, Zhou YJ, Cheng WJ. Luteolin-induced protection of H2O2-induced apoptosis in PC12 cells and the associated pathway. Mol Med Rep. 2015;12:7699–704.

    Article  CAS  PubMed  Google Scholar 

  • Lukiw WJ, Zhao Y, Cui JG. An NF-κB-sensitive micro RNA-146a-mediated inflammatory circuit in Alzheimer disease and in stressed human brain cells. J Biol Chem. 2008;283:31315–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lv R, Du L, Lu C, Wu J, Ding M, Wang C, et al. Allicin protects against H2O2-induced apoptosis of PC12 cells via the mitochondrial pathway. Exp Ther Med. 2017;14:2053–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ouyang YB, Xu L, Yue S, Liu S, Giffard RG. Neuroprotection by astrocytes in brain ischemia: importance of microRNAs. Neurosci Lett. 2014;565:53–8.

    Article  CAS  PubMed  Google Scholar 

  • Patel M. Targeting oxidative stress in central nervous system disorders. Trends Pharmacol Sci. 2016;37:768–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rani V, Deep G, Singh RK, Palle K, Yadav UC. Oxidative stress and metabolic disorders: pathogenesis and therapeutic strategies. Life Sci. 2016;148:183–93.

    Article  CAS  Google Scholar 

  • Shaker ME, Hazem SH, Ashamallah SA. Inhibition of the JAK/STAT pathway by ruxolitinib ameliorates thioacetamide-induced hepatotoxicity. Food Chem Toxicol. 2016;96:290–301.

    Article  CAS  PubMed  Google Scholar 

  • Shao Y, Yu Y, Zhou Q, Li C, Yang L, Pei CG. Inhibition of miR-134 protects against hydrogen peroxide-induced apoptosis in retinal ganglion cells. J Mol Neurosci. 2015;56:461–71.

    Article  CAS  PubMed  Google Scholar 

  • Shenoy AR, Kirschnek S, Häcker G. IL-15 regulates Bcl-2 family members Bim and Mcl-1 through JAK/STAT and PI3K/AKT pathways in T cells. Eur J Immunol. 2014;44:2500–7.

    Article  CAS  PubMed  Google Scholar 

  • Visavadiya NP, Patel SP, Vanrooyen JL, Sullivan PG, Rabchevsky AG. Cellular and subcellular oxidative stress parameters following severe spinal cord injury. Redox Biol. 2016;8:59–67.

    Article  CAS  PubMed  Google Scholar 

  • Wang M, Li Y, Ding Y, Zhang H, Sun T, Zhang K, et al. Silibinin prevents autophagic cell death upon oxidative stress in cortical neurons and cerebral ischemia-reperfusion injury. Mol Neurobiol. 2016;53:932–43.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This study was supported by the Science and Technology Project of Shandong Province (No. 2011YD18006 and No. J16LL58).

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Authors and Affiliations

  1. Department of Urology, The Affiliated Hospital of Qingdao University, Qingdao, 266003, China

    Xuecheng Yang, Xin Mao, Xuemei Ding, Fengju Guan, Yuefeng Jia, Lei Luo, Bin Li & Hailin Tan

  2. Department of Endocrinology, The Affiliated Hospital of Qingdao University, No. 16 of Jiangsu Road, Qingdao, 266003, China

    Caixia Cao

Authors
  1. Xuecheng Yang
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  2. Xin Mao
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  3. Xuemei Ding
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  4. Fengju Guan
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  5. Yuefeng Jia
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  6. Lei Luo
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  7. Bin Li
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  8. Hailin Tan
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  9. Caixia Cao
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Contributions

This work was designed and conceived by Xuecheng Yang and Caixia Cao. The experiments were carried out by Xuecheng Yang, Bin Li, Lei Luo, and Hailin Tan. Data were interpreted by Xin Mao, Yuefeng Jia, and Xuemei Ding. The manuscript was prepared and reviewed by Xuecheng Yang, Fengju Guan, and Caixia Cao.

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Correspondence to Caixia Cao.

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Yang, X., Mao, X., Ding, X. et al. miR-146a down-regulation alleviates H2O2-induced cytotoxicity of PC12 cells by regulating MCL1/JAK/STAT pathway. Cell Biol Toxicol 34, 479–489 (2018). https://doi.org/10.1007/s10565-018-9424-2

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  • DOI: https://doi.org/10.1007/s10565-018-9424-2

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