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Current Neurovascular Research

Author(s): Liao Qi*, Ming Jiang-Hua, Hu Ge-Liang, Chen Qing and Li Ya-Ming

DOI: 10.2174/1567202616666190906102343

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MiR-34a Inhibits Spinal Cord Injury and Blocks Spinal Cord Neuron Apoptosis by Activating Phatidylinositol 3-kinase (PI3K)/AKT Pathway Through Targeting CD47

Page: [373 - 381] Pages: 9

  • * (Excluding Mailing and Handling)

Abstract

Objective: Dysregulation of miR-34a has been reported for its implication in neuronal development. This study aims to explore the effect and possible mechanism of miR-34a on neuron apoptosis induced by Spinal Cord Injury (SCI).

Materials and Methods: SCI model was established using Allen's weight-drop method and rats in the sham group were performed with laminectomy without weight-drop injury. Basso Bcattie Bresnahan (BBB) rating scale was applied to evaluate the locomotor function of rats. Pathological changes of spinal cord tissues in SCI rats were observed after hematoxylin and eosin (HE) staining. Rats were separately injected with miR-34a agomir, miR-34a agomir NC, si-CD47 and si- CD47 NC before their spinal cord tissues were collected for terminal-deoxynucleoitidyl Transferase Mediated nick end labeling (TUNEL) staining. Expressions of miR-34a, si-CD47, apoptosis related proteins and AKT pathway related proteins were measured by quantitative reverse transcription- polymerase chain reaction (qRT-PCR) and western blot.

Results: SCI rat models were successfully established evidenced by decreased BBB scores and HE staining. Injection of miR-34a agomir and/or si-CD47 could suppress neuron cell apoptosis, with deceased apoptotic index (AI) and pro-apoptotic protein (cleaved caspase-3 and Bax) levels, and increased expressions of anti-apoptotic proteins (Bcl-2 and Mcl-1). Phosphorylated levels of phatidylinositol 3-kinase (PI3K) and AKT were further increased in rats injected with miR-34a agomir and si-CD47, compared with miR-34a agomir or si-CD47 injection alone.

Conclusion: MiR-34a can downregulate CD47 expression to activate PI3K/AKT signal pathway, and thus inhibit SCI induced spinal neuron apoptosis.

Keywords: Spinal cord injury, miR-34a, CD47, apoptosis, AKT pathway, miRNA, glial cells.

[1]
Nieto-Diaz M, Esteban FJ, Reigada D, et al. MicroRNA dysregulation in spinal cord injury: Causes, consequences and therapeutics. Front Cell Neurosci 2014; 8(53): 53.
[http://dx.doi.org/10.3389/fncel.2014.00053]
[2]
Jain NB, Ayers GD, Peterson EN, et al. Traumatic spinal cord injury in the United States, 1993-2012. JAMA 2015; 313(22): 2236-43.
[http://dx.doi.org/10.1001/jama.2015.6250] [PMID: 26057284]
[3]
Lv CL, Zhang T, Yan TZ, Yi GK, Gao K. MicroRNA-448 inhibits the regeneration of spinal cord injury through PI3K/AKT/Bcl-2 axis. Eur Rev Med Pharmacol Sci 2019; 23(7): 2719-26.
[PMID: 31002121]
[4]
Silva NA, Sousa N, Reis RL, et al. From basics to clinical: A comprehensive review on spinal cord injury. Prog Neurobiol 2014; 114: 25-57.
[http://dx.doi.org/10.1016/j.pneurobio.2013.11.002]
[5]
Li J, Liang Z, Wang S, et al. Study on the pathological and biomedical characteristics of spinal cord injury by confocal Raman microspectral imaging. Spectrochim Acta A Mol Biomol Spectrosc 2019; 210: 148-58.
[http://dx.doi.org/10.1016/j.saa.2018.11.022]
[6]
Ahuja CS, Wilson JR, Nori S, et al. Traumatic spinal cord injury. Nat Rev Dis Primers 2017; 3: 17018.
[7]
Fakhoury M. Spinal cord injury: Overview of experimental approaches used to restore locomotor activity. Rev Neurosci 2015; 26(4): 397-405.
[http://dx.doi.org/10.1515/revneuro-2015-0001] [PMID: 25870961]
[8]
Yan H, Hong P, Jiang M, Li H. MicroRNAs as potential therapeutics for treating spinal cord injury. Neural Regen Res 2012; 7(17): 1352-9.
[PMID: 25657667]
[9]
Shi Z, Zhou H, Lu L, et al. The roles of microRNAs in spinal cord injury. Int J Neurosci 2017; 127(12): 1104-15.
[http://dx.doi.org/10.1080/00207454.2017.1323208] [PMID: 28436759]
[10]
Zhou S, Ding F, Gu X. Non-coding RNAs as emerging regulators of neural injury responses and regeneration. Neurosci Bull 2016; 32(3): 253-64.
[http://dx.doi.org/10.1007/s12264-016-0028-7] [PMID: 27037691]
[11]
Mai EH, Lei T, Li SQ, et al. MiR-34a affects hepatocyte proliferation during hepatocyte regeneration through regulating Notch/HIF-1α signaling pathway. Eur Rev Med Pharmacol Sci 2019; 23(8): 3503-11.
[PMID: 31081106]
[12]
Shetty SK, Tiwari N, Marudamuthu AS, et al. p53 and miR-34a feedback promotes lung epithelial injury and pulmonary fibrosis. Am J Pathol 2017; 187(5): 1016-34.
[http://dx.doi.org/10.1016/j.ajpath.2016.12.020] [PMID: 28273432]
[13]
Fu BC, Lang JL, Zhang DY, et al. Suppression of miR-34a expression in the myocardium protects against ischemia-reperfusion injury through SIRT1 protective pathway. Stem Cells Dev 2017; 26(17): 1270-82.
[http://dx.doi.org/10.1089/scd.2017.0062] [PMID: 28599575]
[14]
Ning B, Gao L, Liu RH, Liu Y, Zhang NS, Chen ZY. microRNAs in spinal cord injury: Potential roles and therapeutic implications. Int J Biol Sci 2014; 10(9): 997-1006.
[http://dx.doi.org/10.7150/ijbs.9058] [PMID: 25210498]
[15]
Chen CH, Sung CS, Huang SY, et al. The role of the PI3K/Akt/mTOR pathway in glial scar formation following spinal cord injury. Exp Neurol 2016; 278: 27-41.
[16]
Zhang W, Hsu P, Zhong B, et al. MiR-34a enhances chondrocyte apoptosis, senescence and facilitates development of osteoarthritis by targeting DLL1 and regulating PI3K/AKT pathway. Cell Physiol Biochem 2018; 48(3): 1304-16.
[http://dx.doi.org/10.1159/000492090] [PMID: 30048987]
[17]
Bai J, Wu J, Tang R, et al. Emodin, a natural anthraquinone, suppresses liver cancer in vitro and in vivo by regulating VEGFR2 and miR-34a. Invest New Drugs 2019. [Epub ahead of Print]
[http://dx.doi.org/10.1007/s10637-019-00777-5] [PMID: 30976957]
[18]
Kouhsar M, Azimzadeh Jamalkandi S, Moeini A, Masoudi-Nejad A. Detection of novel biomarkers for early detection of non-muscle-invasive bladder cancer using competing endogenous RNA network analysis. Sci Rep 2019; 9(1): 8434.
[http://dx.doi.org/10.1038/s41598-019-44944-3] [PMID: 31182759]
[19]
Zhu M, Zheng Z, Huang J, et al. Modulation of miR-34a in curcumin-induced antiproliferation of prostate cancer cells. J Cell Biochem 2019; 120(9): 15616-24.
[http://dx.doi.org/10.1002/jcb.28828] [PMID: 31042325]
[20]
Jung SY, Kim DY, Yune TY, Shin DH, Baek SB, Kim CJ. Treadmill exercise reduces spinal cord injury-induced apoptosis by activating the PI3K/Akt pathway in rats. Exp Ther Med 2014; 7: 587-93.
[http://dx.doi.org/10.3892/etm.2013.1451] [PMID: 24520250]
[21]
Singh A, Tetreault L, Kalsi-Ryan S, et al. Global prevalence and incidence of traumatic spinal cord injury. Clin Epidemiol 2014; 6: 309-31.
[22]
Assinck P, Duncan GJ, Hilton BJ, Plemel JR, Tetzlaff W. Cell transplantation therapy for spinal cord injury. Nat Neurosci 2017; 20(5): 637-47.
[http://dx.doi.org/10.1038/nn.4541] [PMID: 28440805]
[23]
Chen Y, Cao S, Xu P, et al. Changes in the expression of miR-34a and its target genes following spinal cord injury in rats. Med Sci Monit 2016; 22: 3981-93.
[http://dx.doi.org/10.12659/MSM.900893]
[24]
Zhu H, Xie R, Liu X, et al. MicroRNA-494 improves functional recovery and inhibits apoptosis by modulating PTEN/AKT/mTOR pathway in rats after spinal cord injury. Biomed Pharmacother 2017; 92: 879-87.
[25]
Zhang T, Ni S, Luo Z, Lang Y, Hu J, Lu H. The protective effect of microRNA-21 in neurons after spinal cord injury. Spinal Cord 2019; 57(2): 141-9.
[http://dx.doi.org/10.1038/s41393-018-0180-1] [PMID: 30089893]
[26]
Agostini M, Tucci P, Steinert JR, et al. microRNA-34a regulates neurite outgrowth, spinal morphology, and function. Proc Natl Acad Sci USA 2011; 108(52): 21099-104.
[http://dx.doi.org/10.1073/pnas.1112063108] [PMID: 22160706]
[27]
Barrera L, Montes-Servín E, Hernandez-Martinez JM, et al. CD47 overexpression is associated with decreased neutrophil apoptosis/phagocytosis and poor prognosis in non-small-cell lung cancer patients. Br J Cancer 2017; 117(3): 385-97.
[http://dx.doi.org/10.1038/bjc.2017.173] [PMID: 28632731]
[28]
Kong F, Gao F, Li H, et al. CD47: A potential immunotherapy target for eliminating cancer cells. Clin Transl Oncol 2016; 18(11): 1051-5.
[http://dx.doi.org/10.1007/s12094-016-1489-x] [PMID: 26830085]
[29]
Wang HS, Pei F, Chen Z, Zhang L. Increased apoptosis of inflamed odontoblasts is associated with CD47 loss. J Dent Res 2016; 95(6): 697-703.
[http://dx.doi.org/10.1177/0022034516633639] [PMID: 26912219]
[30]
Sick E, Boukhari A, Deramaudt T, et al. Activation of CD47 receptors causes proliferation of human astrocytoma but not normal astrocytes via an Akt-dependent pathway. Glia 2011; 59(2): 308-19.
[http://dx.doi.org/10.1002/glia.21102] [PMID: 21125662]
[31]
Li F, Zhou MW. MicroRNAs in contusion spinal cord injury: pathophysiology and clinical utility. Acta Neurol Belg 2019; 119(1): 21-7.
[http://dx.doi.org/10.1007/s13760-019-01076-9] [PMID: 30790223]
[32]
Wu Q, Yi X. Down-regulation of long noncoding RNA MALAT1 protects hippocampal neurons against excessive autophagy and apoptosis via the PI3K/Akt signaling pathway in rats with epilepsy. J Mol Neurosci 2018; 65(2): 234-45.
[http://dx.doi.org/10.1007/s12031-018-1093-3] [PMID: 29858824]
[33]
Zhang K, Wu S, Li Z, Zhou J. MicroRNA-211/BDNF axis regulates LPS-induced proliferation of normal human astrocyte through PI3K/AKT pathway. Biosci Rep 2017; 37(4)BSR20170755
[http://dx.doi.org/10.1042/BSR20170755] [PMID: 28790168]
[34]
Wang T, Li B, Wang Z, et al. miR-155-5p promotes dorsal root ganglion neuron axonal growth in an inhibitory microenvironment via the cAMP/PKA Pathway. Int J Biol Sci 2019; 15(7): 1557-70. [https://www.ncbi.nlm.nih.gov/pubmed/31337984]
[PMID: 31337984]
[35]
Zhao CL, Cui HA, Zhang XR. MiR-543-5p inhibits inflammation and promotes nerve regeneration through inactivation of the NF-kappaB in rats after spinal cord injury. Eur Rev Med Pharmacol Sci 2019; 23(3)(Suppl.): 39-46. [https://www.ncbi.nlm.nih.gov/pubmed/31389572]
[PMID: 31389572]