Long Non-coding RNA in CNS Injuries: A New Target for Therapeutic Intervention
2019; Cell Press; Volume: 17; Linguagem: Inglês
10.1016/j.omtn.2019.07.013
ISSN2162-2531
Autores Tópico(s)Cancer-related molecular mechanisms research
ResumoCNS injuries, such as traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and cerebral ischemic stroke, are important causes of death and long-term disability worldwide. As an important class of pervasive genes involved in many pathophysiological processes, long non-coding RNAs (lncRNAs) have received attention in the past decades. Multiple studies indicate that lncRNAs are abundant in the CNS and have a key role in brain function as well as many neurological disorders, especially in CNS injuries. Several investigations have deciphered that regulation of lncRNAs exert pro-angiogenesis, anti-apoptosis, and anti-inflammation effects in CNS injury via different molecules and pathways, including microRNA (miRNA), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT), Notch, and p53. Thus, lncRNAs show great promise as molecular targets in CNS injuries. In this article, we provide an updated review of the current state of our knowledge about the relationship between lncRNAs and CNS injuries, highlighting the specific roles of lncRNAs in CNS injuries. CNS injuries, such as traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and cerebral ischemic stroke, are important causes of death and long-term disability worldwide. As an important class of pervasive genes involved in many pathophysiological processes, long non-coding RNAs (lncRNAs) have received attention in the past decades. Multiple studies indicate that lncRNAs are abundant in the CNS and have a key role in brain function as well as many neurological disorders, especially in CNS injuries. Several investigations have deciphered that regulation of lncRNAs exert pro-angiogenesis, anti-apoptosis, and anti-inflammation effects in CNS injury via different molecules and pathways, including microRNA (miRNA), nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B (PI3K/AKT), Notch, and p53. Thus, lncRNAs show great promise as molecular targets in CNS injuries. In this article, we provide an updated review of the current state of our knowledge about the relationship between lncRNAs and CNS injuries, highlighting the specific roles of lncRNAs in CNS injuries. CNS injuries are one of the leading causes of disability and death in modern society, resulting in high medical costs.1Wang Y. Tan H. Hui X. Biomaterial Scaffolds in Regenerative Therapy of the Central Nervous System.BioMed Res. Int. 2018; 2018: 7848901PubMed Google Scholar CNS injuries usually include traumatic brain injury (TBI), subarachnoid hemorrhage (SAH), intracerebral hemorrhage (ICH), and cerebral ischemic stroke.2Huang H. Young W. Chen L. Feng S. Zoubi Z.M.A. Sharma H.S. Saberi H. Moviglia G.A. He X. Muresanu D.F. et al.Clinical Cell Therapy Guidelines for Neurorestoration (IANR/CANR 2017).Cell Transplant. 2018; 27: 310-324Crossref PubMed Scopus (17) Google Scholar The pathological processes of CNS injuries include a series of neurological events, such as inflammation, oxidative stress, apoptosis, autophagy, and blood-brain barrier (BBB) disruption, and eventually result in neuronal cell death in the brain.3Boguszewska-Czubara A. Budzynska B. Skalicka-Wozniak K. Kurzepa J. Perspectives and new aspects of metalloproteinases' inhibitors in therapy of CNS disorders: from chemistry to medicine.Curr. Med. Chem. 2018; (Published online May 13, 2018)https://doi.org/10.2174/0929867325666180514111500Crossref PubMed Scopus (9) Google Scholar Despite the efforts on searching effective methods, patients suffering with severe CNS injuries always end up with poor prognosis. Therefore, new and effective strategies of treatment are urgently needed to reduce the heavy disease and economic burden. Long non-coding RNAs (lncRNAs) are known as non-coding RNA transcripts greater than 200 nucleotides.4Roberts T.C. Morris K.V. Weinberg M.S. Perspectives on the mechanism of transcriptional regulation by long non-coding RNAs.Epigenetics. 2014; 9: 13-20Crossref PubMed Scopus (113) Google Scholar Although lncRNAs were primarily considered as simply transcriptional by-products, accumulated evidence suggests that lncRNAs participate in regulation of various physiological and pathophysiological processes, such as immunity, inflammation, cell differentiation, proliferation, and survival, by modulating the stability and nuclear retention of their target genes.5Lee K.T. Nam J.W. Post-transcriptional and translational regulation of mRNA-like long non-coding RNAs by microRNAs in early developmental stages of zebrafish embryos.BMB Rep. 2017; 50: 226-231Crossref PubMed Scopus (0) Google Scholar lncRNAs regulate gene expression at epigenetic, transcriptional, post-transcriptional, and chromatin remodeling levels,6Bali K.K. Kuner R. Noncoding RNAs: key molecules in understanding and treating pain.Trends Mol. 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Delgado R.N. Park K.Y. Gonzales-Roybal G. Oldham M.C. Song J.S. Lim D.A. Integration of genome-wide approaches identifies lncRNAs of adult neural stem cells and their progeny in vivo.Cell Stem Cell. 2013; 12: 616-628Abstract Full Text Full Text PDF PubMed Scopus (193) Google Scholar, 15Mercer T.R. Dinger M.E. Sunkin S.M. Mehler M.F. Mattick J.S. Specific expression of long noncoding RNAs in the mouse brain.Proc. Natl. Acad. Sci. USA. 2008; 105: 716-721Crossref PubMed Scopus (927) Google Scholar, 16Hong S.H. Kwon J.T. Kim J. Jeong J. Kim J. Lee S. Cho C. Profiling of testis-specific long noncoding RNAs in mice.BMC Genomics. 2018; 19: 539Crossref PubMed Scopus (6) Google Scholar The altered expression of lncRNAs was involved in brain development and functional diversification and contributed to diverse neurological disorders such as CNS injuries.17Qureshi I.A. Mehler M.F. Emerging roles of non-coding RNAs in brain evolution, development, plasticity and disease.Nat. Rev. Neurosci. 2012; 13: 528-541Crossref PubMed Scopus (437) Google Scholar, 18Spadaro P.A. Bredy T.W. Emerging role of non-coding RNA in neural plasticity, cognitive function, and neuropsychiatric disorders.Front. Genet. 2012; 3: 132Crossref PubMed Scopus (31) Google Scholar In addition, many gain- and loss-of-function approaches found that lncRNAs played an important role in CNS injury-induced secondary brain damage.19He D. Wang J. Lu Y. Deng Y. Zhao C. Xu L. Chen Y. Hu Y.C. Zhou W. Lu Q.R. lncRNA Functional Networks in Oligodendrocytes Reveal Stage-Specific Myelination Control by an lncOL1/Suz12 Complex in the CNS.Neuron. 2017; 93: 362-378Abstract Full Text Full Text PDF PubMed Scopus (79) Google Scholar In this regard, highlighting the potentially functional roles of lncRNAs in CNS injuries is important. In the present study, we provide an overview of lncRNA functions in CNS injuries and the associated molecular mechanisms. During studies assessing the functions of lncRNAs, it was revealed that lncRNAs may act as potential onco- or tumor-suppressor RNAs in numerous cancer types.20Shi X. Sun M. Liu H. Yao Y. Song Y. Long non-coding RNAs: a new frontier in the study of human diseases.Cancer Lett. 2013; 339: 159-166Crossref PubMed Scopus (976) Google Scholar This observation led to investigations into the potential role of lncRNAs in various models. Recently, the roles of lncRNAs in CNS injuries were elucidated. Numbers of aberrantly expressed lncRNAs were identified using techniques such as microarray or RNA sequencing (RNA-seq).21Dykstra-Aiello C. Jickling G.C. Ander B.P. Shroff N. Zhan X. Liu D. Hull H. Orantia M. Stamova B.S. Sharp F.R. Altered Expression of Long Noncoding RNAs in Blood After Ischemic Stroke and Proximity to Putative Stroke Risk Loci.Stroke. 2016; 47: 2896-2903Crossref PubMed Scopus (98) Google Scholar, 22Zhang J. Yuan L. Zhang X. Hamblin M.H. Zhu T. Meng F. Li Y. Chen Y.E. Yin K.J. Altered long non-coding RNA transcriptomic profiles in brain microvascular endothelium after cerebral ischemia.Exp. Neurol. 2016; 277: 162-170Crossref PubMed Scopus (158) Google Scholar Specifically, lncRNAs such as metastasis associated lung adenocarcinoma transcript 1 (MALAT1), maternally expressed gene 3 (MEG3), brain-derived neurotrophic factor antisense RNA (BDNF-AS), nuclear enriched abundant transcript 1 (NEAT1), growth arrest-specific transcript 5 (GAS5), and CAMK2D-associated transcript 1 (C2dat1) were found to affect secondary brain injury in CNS injury models (Table 1).Table 1The Functions and Molecular Targets of lncRNAs in CNS InjurieslncRNAsModelsAnimals and/or CellsExpressionBeneficial Functions of the Regulation of lncRNAsMolecular TargetsANRILMACOrats, HUVECsincreasedpromote angiogenesis, decrease infarction and inflammationNF-κBBDNF-ASH/R injuryHCNs, human astrocytesincreasedincrease MMP, ameliorate apoptosisPI3K/AKTC2dat1I/R injurymice, mouse neuronsincreasedpromote neuronal survival, decrease inflammationNF-κBFosDTMCAOratsincreasedameliorate motor deficits, reduce infarct volumeRESTGAS5HIBDrats, rat neuronsincreasedreduce brain infarct size, improve neurological function recoverymiR-23aGm4419TBImouse astrocytesincreaseddecrease inflammation, improve neurological deficitsmiR-4661OGD/R injuryrat microglial cellsincreasedreduce neuroinflammationNF-κBH19OGD/R injurymiceincreasedattenuate neurological deficits and inflammation–I/R injuryrats, SH-SY5Y cellsincreaseddecrease cell death and autophagy–MALAT1OGD/R injurymice, mouse neuronsincreasedattenuate autophagy, protect BBB functionmiR-30aBMECsincreasedpromote autophagy, inhibit cell death and apoptosismiR-26b, PI3K/AKTMEG3hypoxic injuryPC12 cellsincreasedattenuate cell injury and apoptosismiR-147MCAOmice, rats, HMECsincreasedameliorate brain lesion, promote angiogenesisNotch, miR-181bSAHrats, rat neuronsincreaseddecrease cell death and apoptosisPI3K/AKTOGD/R injuryHT22 cellsincreasedimprove neurological function, attenuate apoptosismiR-181bN1LRI/R injuryratsincreasedenhance proliferation, inhibit apoptosis, protect BBB functionp53OGD/R injuryN2a cellsNEAT1TBIratsincreasedimprove neurological function, reduce cell death–NKILAICHrats, rat neuronsdecreasedinduce autophagy, decrease inflammationNF-κBRMSTOGD/R injurymouse neuronsincreasedreduce brain infarct size, improve neurological function–MCAOmiceSNHG1OGD/R injuryBMECsincreasedpromote cell survival and angiogenesismiR-199aTUG1MACOratsincreaseddecrease cell apoptosis, improve BBB functionmiR-9OGD/R injuryrat neuronslncRNAs, long non-coding RNAs; ANRIL, antisense non-coding RNA in the INK4 locus; MCAO, middle cerebral artery occlusion; HUVECs, human umbilical vein endothelial cells; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; BDNF-AS, brain-derived neurotrophic factor antisense RNA; H/R, hypoxia-reoxygenation; HCNs, human cortical neurons; MMP, mitochondrial membrane potential; PI3K/AKT, phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B; C2dat1, CaMK2D-associated transcript 1; I/R, ischemia-reperfusion; FosDT, Fos downstream transcript; GAS5, growth arrest-specific transcript 5; HIBD, hypoxic/ischemic brain damage; miRNAs, microRNAs; OGD/R, oxygen-glucose deprivation/reoxygenation; TBI, traumatic brain injury; MALAT1, metastasis-associate lung adenocarcinoma transcript 1; BMECs, brain microvascular endothelial cells; MEG3, maternally expressed gene 3; HMECs, human microvascular endothelial cells; SAH, subarachnoid hemorrhage; NEAT1, nuclear enriched abundant transcript 1; ICH, intracerebral hemorrhage; RMST, rhabdomyosarcoma 2-associated transcript; SNHG1, small nucleolar RNA host gene 1; TUG1, taurine-upregulated gene 1. Open table in a new tab lncRNAs, long non-coding RNAs; ANRIL, antisense non-coding RNA in the INK4 locus; MCAO, middle cerebral artery occlusion; HUVECs, human umbilical vein endothelial cells; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; BDNF-AS, brain-derived neurotrophic factor antisense RNA; H/R, hypoxia-reoxygenation; HCNs, human cortical neurons; MMP, mitochondrial membrane potential; PI3K/AKT, phosphatidylinositol-4,5-bisphosphate 3-kinase/protein kinase B; C2dat1, CaMK2D-associated transcript 1; I/R, ischemia-reperfusion; FosDT, Fos downstream transcript; GAS5, growth arrest-specific transcript 5; HIBD, hypoxic/ischemic brain damage; miRNAs, microRNAs; OGD/R, oxygen-glucose deprivation/reoxygenation; TBI, traumatic brain injury; MALAT1, metastasis-associate lung adenocarcinoma transcript 1; BMECs, brain microvascular endothelial cells; MEG3, maternally expressed gene 3; HMECs, human microvascular endothelial cells; SAH, subarachnoid hemorrhage; NEAT1, nuclear enriched abundant transcript 1; ICH, intracerebral hemorrhage; RMST, rhabdomyosarcoma 2-associated transcript; SNHG1, small nucleolar RNA host gene 1; TUG1, taurine-upregulated gene 1. MALAT1, a well conserved, stable, and abundant lncRNA (6.5 kb), was initially considered to be upregulated in solid tumors and associated with cancer cell proliferation, metastasis, survival, and recurrence.23Chang J. Xu W. Du X. Hou J. MALAT1 silencing suppresses prostate cancer progression by upregulating miR-1 and downregulating KRAS.OncoTargets Ther. 2018; 11: 3461-3473Crossref PubMed Scopus (50) Google Scholar However, growing evidence indicates that MALAT1 has a special role in regeneration after brain injury. It was abundantly expressed in vascular endothelial cells, skeletal muscle, and cardiomyocytes and participated in the pathological inflammatory processes, proliferation, differentiation, myogenesis, and angiogenesis.24Qiao Y. Peng C. Li J. Wu D. Wang X. LncRNA MALAT1 is neuroprotective in a rat model of spinal cord ischemia-reperfusion injury through miR-204 regulation.Curr. Neurovasc. Res. 2018; 15: 211-219Crossref PubMed Scopus (7) Google Scholar It has been shown that MALAT1 could protect brain microvascular endothelial cells (BMECs) from injury caused by oxygen-glucose deprivation-reoxygenation by serving as an autophagy inducer.25Li Z. Li J. Tang N. Long noncoding RNA Malat1 is a potent autophagy inducer protecting brain microvascular endothelial cells against oxygen-glucose deprivation/reoxygenation-induced injury by sponging miR-26b and upregulating ULK2 expression.Neuroscience. 2017; 354: 1-10Crossref PubMed Scopus (0) Google Scholar In addition, the role of MALAT1 in endothelial cell damage and hyperglycemia-induced inflammation has been previously reported.26Puthanveetil P. Chen S. Feng B. Gautam A. Chakrabarti S. Long non-coding RNA MALAT1 regulates hyperglycaemia induced inflammatory process in the endothelial cells.J. Cell. Mol. Med. 2015; 19: 1418-1425Crossref PubMed Scopus (293) Google Scholar MEG3 is an ∼1.6 kb imprinted gene belonging to the imprinted DLK1-MEG3 locus located at chromosome 14q32.3 DLK1 locus in humans. There are 12 different MEG3 gene transcripts generated by alternative splicing, and the MEG3 gene encodes a non-coding RNA of approximately 1700 nucleotides.27Mondal T. Subhash S. Vaid R. Enroth S. Uday S. Reinius B. Mitra S. Mohammed A. James A.R. Hoberg E. et al.MEG3 long noncoding RNA regulates the TGF-β pathway genes through formation of RNA-DNA triplex structures.Nat. Commun. 2015; 6: 7743Crossref PubMed Google Scholar MEG3 was first identified as a lncRNA with the function of a tumor suppressor.28Ji L. Li X. Long noncoding RNA MEG3 is a tumor suppressor in choriocarcinoma by upregulation of microRNA-211.J Cell Physiol. 2019; (Published online May 23, 2019)https://doi.org/10.1002/jcp.28853Crossref Scopus (14) Google Scholar Subsequent results revealed that MEG3 may be involved in cellular remodeling and necessary for the neurons to resist injuries.29Liu J. Li Q. Zhang K.S. Hu B. Niu X. Zhou S.M. Li S.G. Luo Y.P. Wang Y. Deng Z.F. Downregulation of the Long Non-Coding RNA Meg3 Promotes Angiogenesis After Ischemic Brain Injury by Activating Notch Signaling.Mol. Neurobiol. 2017; 54: 8179-8190Crossref PubMed Scopus (99) Google Scholar Altered expression of MEG3 was observed to mediate ischemic neuronal death by activating p53 both in vitro and in vivo.30Bao M.H. Szeto V. Yang B.B. Zhu S.Z. Sun H.S. Feng Z.P. Long non-coding RNAs in ischemic stroke.Cell Death Dis. 2018; 9: 281Crossref PubMed Scopus (163) Google Scholar Moreover, downregulation of MEG3 could protect against ischemic damage and enhance neurobehavioral outcomes.29Liu J. Li Q. Zhang K.S. Hu B. Niu X. Zhou S.M. Li S.G. Luo Y.P. Wang Y. Deng Z.F. Downregulation of the Long Non-Coding RNA Meg3 Promotes Angiogenesis After Ischemic Brain Injury by Activating Notch Signaling.Mol. Neurobiol. 2017; 54: 8179-8190Crossref PubMed Scopus (99) Google Scholar Furthermore, MEG3 functioned as a competing endogenous RNA for miR-181b to regulate 12/15-LOX expression in middle cerebral artery occlusion-induced ischemic infarct of brain nerve cells.31Liu X. Hou L. Huang W. Gao Y. Lv X. Tang J. The Mechanism of Long Non-coding RNA MEG3 for Neurons Apoptosis Caused by Hypoxia: Mediated by miR-181b-12/15-LOX Signaling Pathway.Front. Cell. Neurosci. 2016; 10: 201Crossref PubMed Scopus (63) Google Scholar BDNF is a member of the neurotrophin family of growth factors. It is abundantly expressed during embryonic development and contributes to the development of the nervous system by synchronizing neuronal and glial maturation as well as participating in axonal and dendritic differentiation.32Marler K.J. Suetterlin P. Dopplapudi A. Rubikaite A. Adnan J. Maiorano N.A. Lowe A.S. Thompson I.D. Pathania M. Bordey A. et al.BDNF promotes axon branching of retinal ganglion cells via miRNA-132 and p250GAP.J. Neurosci. 2014; 34: 969-979Crossref PubMed Scopus (70) Google Scholar In the brain, BDNF acts on neurons in the hippocampus, cortex, and basal forebrain—areas vital to learning, memory, and higher thinking, supporting neuronal growth, differentiation, plasticity, and survival.33Song J.H. Yu J.T. Tan L. Brain-Derived Neurotrophic Factor in Alzheimer's Disease: Risk, Mechanisms, and Therapy.Mol. Neurobiol. 2015; 52: 1477-1493Crossref PubMed Scopus (66) Google Scholar Thus, upregulation of BDNF is thought to have beneficial effects on neurological disorders.34Sona C. Kumar A. Dogra S. Kumar B.A. Umrao D. Yadav P.N. Docosahexaenoic acid modulates brain-derived neurotrophic factor via GPR40 in the brain and alleviates diabesity-associated learning and memory deficits in mice.Neurobiol. Dis. 2018; 118: 94-107Crossref PubMed Scopus (29) Google Scholar BDNF-AS is one type of lncRNA transcribed by RNA polymerase II without an open reading frame.35Modarresi F. Faghihi M.A. Lopez-Toledano M.A. Fatemi R.P. Magistri M. Brothers S.P. van der Brug M.P. Wahlestedt C. Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation.Nat. Biotechnol. 2012; 30: 453-459Crossref PubMed Scopus (480) Google Scholar Chromatin immunoprecipitation results showed that BDNF-AS reduced the localization of EZH2 and H3K27me3 in the BDNF promoter region and inhibited the expression of BDNF, thereby affecting the growth and differentiation of neural cells. Inhibition of BDNF-AS led to increased protein levels of BDNF and induced neuronal growth and differentiation.35Modarresi F. Faghihi M.A. Lopez-Toledano M.A. Fatemi R.P. Magistri M. Brothers S.P. van der Brug M.P. Wahlestedt C. Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation.Nat. Biotechnol. 2012; 30: 453-459Crossref PubMed Scopus (480) Google Scholar Besides, BDNF-AS was identified to be significantly upregulated in patients with cerebral infarction, whereas BDNF-AS small interfering RNA (siRNA) suppressed hypoxia-reoxygenation (H/R)-induced neurotoxicity through activation of the BDNF.36Zhong J.B. Li X. Zhong S.M. Liu J.D. Chen C.B. Wu X.Y. Knockdown of long noncoding antisense RNA brain-derived neurotrophic factor attenuates hypoxia/reoxygenation-induced nerve cell apoptosis through the BDNF-TrkB-PI3K/Akt signaling pathway.Neuroreport. 2017; 28: 910-916Crossref PubMed Scopus (6) Google Scholar In addition, a recent study has declared that BDNF-AS knockdown was a novel method to prevent neurotoxicity in mouse embryonic neural stem cell (ESC)-derived neurons.37Zheng X. Lin C. Li Y. Ye J. Zhou J. Guo P. Long noncoding RNA BDNF-AS regulates ketamine-induced neurotoxicity in neural stem cell derived neurons.Biomed. Pharmacother. 2016; 82: 722-728Crossref PubMed Scopus (16) Google Scholar NEAT1 is an ∼3.2 kb novel nuclear lncRNA. It localizes to specific nuclear structures called paraspeckles and is essential for the formation and maintenance of paraspeckles.38Liu K. Mao X. Chen Y. Li T. Ton H. Regulatory role of long non-coding RNAs during reproductive disease.Am. J. Transl. Res. 2018; 10: 1-12PubMed Google Scholar Paraspeckles are formed by the binding of paraspeckle protein (PSP)1, PSP2, and p54nrb to the NEAT1 transcriptional start site. The functions of paraspeckles are to mediate the development of corpus luteum and mammary gland as well as modulate cytoplasmic proteins and RNA functions by migrating to the cytoplasm.39Yu X. Li Z. Zheng H. Chan M.T. Wu W.K. NEAT1: A novel cancer-related long non-coding RNA.Cell Prolif. 2017; 50: 50Google Scholar Recently, NEAT1 has been proposed to be distributed in many subcellular regions where no paraspeckles were observed,40Nakagawa S. Naganuma T. Shioi G. Hirose T. Paraspeckles are subpopulation-specific nuclear bodies that are not essential in mice.J. Cell Biol. 2011; 193: 31-39Crossref PubMed Scopus (225) Google Scholar suggesting that NEAT1 may have other functions besides paraspeckle formation. The effects of NEAT1 on brain injuries were also investigated. For example, it has been shown that NEAT1 was downregulated in cortical neurons in response to neuronal activity.41Barry G. Briggs J.A. Hwang D.W. Nayler S.P. Fortuna P.R. Jonkhout N. Dachet F. Maag J.L. Mestdagh P. Singh E.M. et al.The long non-coding RNA NEAT1 is responsive to neuronal activity and is associated with hyperexcitability states.Sci. Rep. 2017; 7: 40127Crossref PubMed Scopus (67) Google Scholar Moreover, NEAT1 promoted brain injury in septic mice by positively regulating nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), while si-NEAT1 transfection could reduce this injury.42Liu W.Q. Wang Y.J. Zheng Y. Chen X. Effects of long non-coding RNA NEAT1 on sepsis-induced brain injury in mice via NF-κB.Eur. Rev. Med. Pharmacol. Sci. 2019; 23: 3933-3939PubMed Google Scholar In addition, NEAT1 has been shown to play a role in protecting cells subjected to lethal harm from undergoing early apoptosis after TBI, suggesting that NEAT1 potentially exerted a regulatory effect on cell apoptosis.43Hirose T. Virnicchi G. Tanigawa A. Naganuma T. Li R. Kimura H. Yokoi T. Nakagawa S. Bénard M. Fox A.H. Pierron G. NEAT1 long noncoding RNA regulates transcription via protein sequestration within subnuclear bodies.Mol. Biol. Cell. 2014; 25: 169-183Crossref PubMed Scopus (291) Google Scholar GAS5 is a lncRNA that hosts a number of small nucleolar RNAs (snoRNAs) within its introns. So it was originally considered that the biological functions of GAS5 were mediated by introns.20Shi X. Sun M. Liu H. Yao Y. Song Y. Long non-coding RNAs: a new frontier in the study of human diseases.Cancer Lett. 2013; 339: 159-166Crossref PubMed Scopus (976) Google Scholar However, recent studies indicate that GAS5 was increased during growth arrest induced by serum starvation or the lack of growth factors.44Simion V. Haemmig S. Feinberg M.W. LncRNAs in vascular biology and disease.Vascul. Pharmacol. 2018; 114: 145-156Crossref PubMed Scopus (14) Google Scholar Moreover, upregulation of GAS5 could cause a slower cell cycle and an increase in cell apoptosis.45Shi X. Sun M. Liu H. Yao Y. Kong R. Chen F. Song Y. A critical role for the long non-coding RNA GAS5 in proliferation and apoptosis in non-small-cell lung cancer.Mol. Carcinog. 2015; 54: E1-E12Crossref PubMed Scopus (249) Google Scholar These results suggeste that GAS5 plays a key role in normal growth arrest and apoptosis. Therefore, GAS5 may also participate in numerous novel and unexpected cellular functions without introns. Recently, the functions of GAS5 in the neural system were discovered. In a previous study, highly expressed GAS5 was observed in rat hippocampus after TBI by microarray and quantitative real-time PCR analysis, suggesting that GAS5 might be involved in TBI pathological processes.46Wang C.F. Zhao C.C. Weng W.J. Lei J. Lin Y. Mao Q. Gao G.Y. Feng J.F. Jiang J.Y. Alteration in Long Non-Coding RNA Expression after Traumatic Brain Injury in Rats.J. Neurotrauma. 2017; 34: 2100-2108Crossref PubMed Scopus (39) Google Scholar Further studies confirmed the pro-apoptotic effect of GAS5 by downregulation of miR-335 and upregulation of Rasa1 in a TBI cell model.47Dai X. Yi M. Wang D. Chen Y. Xu X. Changqin NO. 1 inhibits neuronal apoptosis via suppressing GAS5 expression in a traumatic brain injury mice model.Biol. Chem. 2019; 400: 753-763Crossref PubMed Scopus (2) Google Scholar Besides, GAS5 was shown to be a promising therapeutic target for the treatment of hypoxic/ischemic brain damage (HIBD).48Zhao R.B. Zhu L.H. Shu J.P. Qiao L.X. Xia Z.K. GAS5 silencing protects against hypoxia/ischemia-induced neonatal brain injury.Biochem. Biophys. Res. Commun. 2018; 497: 285-291Crossref PubMed Scopus (28) Google Scholar C2dat1 is a sense lncRNA that overlaps with introns 13–15 and exon 14 of the CaMK2D gene in the genome.49Xu Q. Deng F. Xing Z. Wu Z. Cen B. Xu S. Zhao Z. Nepomuceno R. Bhuiyan M.I. Sun D. et al.Long non-coding RNA C2dat1 regulates CaMKIIδ expression to promote neuronal survival through the NF-κB signaling pathway following cerebral ischemia.Cell Death Dis. 2016; 7: e2173Crossref PubMed Scopus (89) Google Scholar It was first discovered in a lncRNA array analysis of a rat middle cerebral artery occlusion (MCAO) model in 2016.49Xu Q. Deng F. Xing Z. Wu Z. Cen B. Xu S. Zhao Z. Nepomuceno R. Bhuiyan M.I. Sun D. et al.Long non-coding RNA C2dat1 regulates CaMKIIδ expression to promote neuronal survival through the NF-κB signaling pathway following cerebral ischemia.Cell Death Dis. 2016; 7: e2173Crossref PubMed Scopus (89) Google Scholar C2dat1 was mainly located in the nucleus of N2a cells, and the inhibition of C2dat1 led to suppression of CaMK2D mRNA and protein.50Jia D. Niu Y. Li D. Liu Z. lncRNA C2dat1 Promotes Cell Proliferation, Migration, and Invasion by Targeting miR-34a-5p in Osteosarcoma Cells.Oncol. Res. 2018; 26: 753-764Crossref PubMed Scopus (6) Google Scholar These results indicated that C2dat1 may interact with CaMK2D directly. It has been shown that C2dat1 was upregulated in murine ischemia/reperfusion (I/R) models and in mouse neuronal cells upon ischemia oxygen-glucose deprivation/reoxygenation (OGD/R). C2dat1 could regulate the expression of CAMK2D/CaMKIIδ in response to OGD/R and C2dat1-induced CaMKIIδ expression, further promoting neuronal survival by activating the NF-κB signaling pathway.49Xu Q. Deng F. Xing Z. Wu Z. Cen B. Xu S. Zhao Z. Nepomuceno R. Bhuiyan M.I. Sun D. et al.Long non-coding RNA C2dat1 regulates CaMKIIδ expression to promote neuronal survival through the NF-κB signaling pathway following cerebral ischemia.Cell Death Dis. 2016; 7: e2173Crossref PubMed Scopus (89) Google Scholar Besides the six well-studied lncRNAs, there were also other lncRNAs that have been explored in CNS injury models, such as BC048612,51Kaur P. Tan J.R. Karolina D.S. Sepramaniam S. Armugam A. Wong P.T. Jeyaseelan K. A long non-coding RNA, BC048612 and a microRNA, miR-203 coordinate the gene expression of neuronal growth regulator 1 (NEGR1) adhesion protein.Biochim. Biophys. Acta. 2016; 1863: 533-543Crossref PubMed Scopus (8) Google Scholar Uc.173,52Nan A. Zhou X. Chen L. Liu M. Zhang N. Zhang L. Luo Y. Liu Z. Dai L. Jiang Y. A transcribed ultraconserved noncoding RNA, Uc.173, is a key molecul
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