Knockdown of ZFAS1 Inhibits Hippocampal Neurons Apoptosis and Autophagy by Activating the PI3K/AKT Pathway via Up-regulating miR-421 in Epilepsy
Tóm tắt
Epilepsy is a common neurological disease. The dysregulated long noncoding RNAs (lncRNAs) are implicated in epileptogenesis. The aim of this research is to explore the role and mechanism of lncRNA zinc finger antisense 1 (ZFAS1) in status epilepticus (SE)-induced hippocampal neurons injury. SE mice model was established and primary hippocampal neurons were isolated. The expression levels of ZFAS1 and microRNA-421 (miR-421) were detected in hippocampus and hippocampal neurons via quantitative reverse transcription polymerase chain reaction. Hippocampal neurons viability, apoptosis and autophagy were analyzed via Cell Counting Kit-8, flow cytometry and western blot. The target relationship between ZFAS1 and miR-421 was analyzed via dual-luciferase reporter assay. The phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) pathway was blocked by LY294002 and related protein levels were detected via western blot. ZFAS1 expression was elevated in hippocampus and hippocampal neurons from SE mice. Knockdown of ZFAS1 increased SE hippocampal neurons viability and decreased apoptosis and autophagy. ZFAS1 could sponge miR-421. MiR-421 expression was declined in SE mice tissues and cells. Down-regulation of miR-421 abolished the suppressive effect of ZFAS1 knockdown on hippocampal neurons apoptosis and autophagy. Silencing of ZFAS1 induced activation of the PI3K/AKT pathway by up-regulating miR-421. Inhibition of the PI3K/AKT pathway reversed the effect of ZFAS1 knockdown on SE hippocampal neurons apoptosis and autophagy. Interference of ZFAS1 attenuated hippocampal neurons apoptosis and autophagy in SE by increasing miR-421 and activating the PI3K/AKT pathway, indicating a new mechanism for understanding the pathogenesis of SE.
Tài liệu tham khảo
Devinsky O, Vezzani A, O'Brien TJ, Jette N, Scheffer IE, de Curtis M, Perucca P (2018) Epilepsy. Nat Rev Dis Primers 4:18024
Pitkanen A, Loscher W, Vezzani A, Becker AJ, Simonato M, Lukasiuk K, Grohn O, Bankstahl JP, Friedman A, Aronica E, Gorter JA, Ravizza T, Sisodiya SM, Kokaia M, Beck H (2016) Advances in the development of biomarkers for epilepsy. Lancet Neurol 15:843–856
Huberfeld G, Blauwblomme T, Miles R (2015) Hippocampus and epilepsy: findings from human tissues. Rev Neurol (Paris) 171:236–251
Liu YQ, Yu F, Liu WH, He XH, Peng BW (2014) Dysfunction of hippocampal interneurons in epilepsy. Neurosci Bull 30:985–998
Hashemian F, Ghafouri-Fard S, Arsang-Jang S, Mirzajani S, Fallah H, Mehvari HJ, Sayad A, Taheri M (2019) Epilepsy is associated with dysregulation of long non-coding RNAs in the peripheral blood. Front Mol Biosci 6:113
Jiang X, Yang Z, Li Z (2019) Zinc finger antisense 1: a long noncoding RNA with complex roles in human cancers. Gene 688:26–33
Yang G, Han B, Feng T (2019) ZFAS1 knockdown inhibits viability and enhances cisplatin cytotoxicity by up-regulating miR-432-5p in glioma cells. Basic Clin Pharmacol Toxicol 125:518–526
Mo D, Liu W, Li Y, Cui W (2019) Long non-coding RNA zinc finger antisense 1 (ZFAS1) regulates proliferation, migration, invasion, and apoptosis by targeting MiR-7-5p in colorectal cancer. Med Sci Monit 25:5150–5158
Wang M, Ji YQ, Song ZB, Ma XX, Zou YY, Li XS (2019) Knockdown of lncRNA ZFAS1 inhibits progression of nasopharyngeal carcinoma by sponging miR-135a. Neoplasma 66:939–945
Ge HB, Chen S, Huang SR, Zhu J (2019) Long noncoding RNA ZFAS1 acts as an oncogene by targeting miR-193a-3p in human non-small cell lung cancer. Eur Rev Med Pharmacol Sci 23:6516–6523
Han CL, Ge M, Liu YP, Zhao XM, Wang KL, Chen N, Hu W, Zhang JG, Li L, Meng FG (2018) Long non-coding RNA H19 contributes to apoptosis of hippocampal neurons by inhibiting let-7b in a rat model of temporal lobe epilepsy. Cell Death Dis 9:617
Bielefeld P, Mooney C, Henshall DC, Fitzsimons CP (2017) miRNA-mediated regulation of adult hippocampal neurogenesis; implications for epilepsy. Brain Plast 3:43–59
Farooqi AA, Qureshi MZ, Coskunpinar E, Naqvi SK, Yaylim I, Ismail M (2014) MiR-421, miR-155 and miR-650: emerging trends of regulation of cancer and apoptosis. Asian Pac J Cancer Prev 15:1909–1912
Hu TB, Chen HS, Cao MQ, Guo FD, Cheng XY, Han ZB, Li MQ (2018) MicroRNA-421 inhibits caspase-10 expression and promotes breast cancer progression. Neoplasma 65:49–54
Li X, Chen SH, Zeng JW (2019) MiR-421 is overexpressed and promotes cell proliferation in non-small cell lung cancer. Med Princ Pract 29:80–89
Wen X, Han XR, Wang YJ, Wang S, Shen M, Zhang ZF, Fan SH, Shan Q, Wang L, Li MQ, Hu B, Sun CH, Wu DM, Lu J, Zheng YL (2018) MicroRNA-421 suppresses the apoptosis and autophagy of hippocampal neurons in epilepsy mice model by inhibition of the TLR/MYD88 pathway. J Cell Physiol 233:7022–7034
Lee SH, Chun W, Kong PJ, Han JA, Cho BP, Kwon OY, Lee HJ, Kim SS (2006) Sustained activation of Akt by melatonin contributes to the protection against kainic acid-induced neuronal death in hippocampus. J Pineal Res 40:79–85
Duan W, Chen Y, Wang XR (2018) MicroRNA155 contributes to the occurrence of epilepsy through the PI3K/Akt/mTOR signaling pathway. Int J Mol Med 42:1577–1584
Liu AH, Chu M, Wang YP (2019) Up-regulation of Trem2 inhibits hippocampal neuronal apoptosis and alleviates oxidative stress in epilepsy via the PI3K/Akt pathway in mice. Neurosci Bull 35:471–485
Leite JP, Garcia-Cairasco N, Cavalheiro EA (2002) New insights from the use of pilocarpine and kainate models. Epilepsy Res 50:93–103
Peng J, Wang K, Xiang W, Li Y, Hao Y, Guan Y (2019) Rosiglitazone polarizes microglia and protects against pilocarpine-induced status epilepticus. CNS Neurosci Ther 25:1363–1372
Jang HJ, Kim JE, Jeong KH, Lim SC, Kim SY, Cho KO (2019) The neuroprotective effect of Hericium erinaceus extracts in mouse hippocampus after pilocarpine-induced status epilepticus. Int J Mol Sci 20:859
Racine RJ (1972) Modification of seizure activity by electrical stimulation II Motor seizure. Electroencephalogr Clin Neurophysiol 32:281–294
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods 25:402–408
Thijs RD, Surges R, O'Brien TJ, Sander JW (2019) Epilepsy in adults. Lancet 393:689–701
Billakota S, Devinsky O, Kim KW (2019) Why we urgently need improved epilepsy therapies for adult patients. Neuropharmacology 170:107855
Villa C, Lavitrano M, Combi R (2019) Long non-coding RNAs and related molecular pathways in the pathogenesis of epilepsy. Int J Mol Sci 20:4898
Wang L, Song LF, Chen XY, Ma YL, Suo JF, Shi JH, Chen GH (2019) MiR-181b inhibits P38/JNK signaling pathway to attenuate autophagy and apoptosis in juvenile rats with kainic acid-induced epilepsy via targeting TLR4. CNS Neurosci Ther 25:112–122
Wu Q, Yi X (2018) 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 65:234–245
Strasser A, Vaux DL (2018) Viewing BCL2 and cell death control from an evolutionary perspective. Cell Death Differ 25:13–20
Nagata S (2018) Apoptosis and clearance of apoptotic cells. Annu Rev Immunol 36:489–517
Schaaf MB, Keulers TG, Vooijs MA, Rouschop KM (2016) LC3/GABARAP family proteins: autophagy-(un)related functions. FASEB J 30:3961–3978
Salminen A, Kaarniranta K, Kauppinen A (2013) Beclin 1 interactome controls the crosstalk between apoptosis, autophagy and inflammasome activation: impact on the aging process. Ageing Res Rev 12:520–534
Li Q, Han Y, Du J, Jin H, Zhang J, Niu M, Qin J (2018) Alterations of apoptosis and autophagy in developing brain of rats with epilepsy: changes in LC3, P62, Beclin-1 and Bcl-2 levels. Neurosci Res 130:47–55
Heras-Sandoval D, Perez-Rojas JM, Pedraza-Chaverri J (2020) Novel compounds for the modulation of mTOR and autophagy to treat neurodegenerative diseases. Cell Signal 65:109442
Liu Q, Ma H, Sun X, Liu B, Xiao Y, Pan S, Zhou H, Dong W, Jia L (2019) The regulatory ZFAS1/miR-150/ST6GAL1 crosstalk modulates sialylation of EGFR via PI3K/Akt pathway in T-cell acute lymphoblastic leukemia. J Exp Clin Cancer Res 38:199
Wang X, Jin Q, Wang X, Chen W, Cai Z (2019) LncRNA ZFAS1 promotes proliferation and migration and inhibits apoptosis in nasopharyngeal carcinoma via the PI3K/AKT pathway in vitro. Cancer Biomark 26:171–182