Home LncRNA HOTAIR targets miR-126-5p to promote the progression of Parkinson’s disease through RAB3IP
Article
Licensed
Unlicensed Requires Authentication

LncRNA HOTAIR targets miR-126-5p to promote the progression of Parkinson’s disease through RAB3IP

  • Qiuyu Lin , Sen Hou , Yuyin Dai , Nan Jiang and Yingjie Lin ORCID logo EMAIL logo
Published/Copyright: July 19, 2019

Abstract

Parkinson’s disease (PD) is a common neurological disorder characterized by dopaminergic (DA) neuron degeneration and death in the midbrain, and the long noncoding RNA HOTAIR has been shown to affect disease progression in PD. In this study, we aimed to further illustrate the molecular mechanism of HOTAIR in PD. Bioinformatics analysis was utilized to determine the potential downstream targets of HOTAIR in PD. Luciferase assay and the RNA Binding Protein Immunoprecipitation (RIP) assay were used to validate the existence of binding sites between competing endogenous RNAs (ceRNAs). Real-time quantitative polymerase chain reaction (qRT-PCR) and Western blotting indicated that HOTAIR and RAB3IP increased while miR-126-5p decreased in PD cells and PD mice. Additionally, the CCK-8 assay and flow cytometric analysis indicated that the knockdown of HOTAIR and RAB3IP and the overexpression of miR-126-5p significantly increased cell proliferation and reduced apoptosis in PD cells. Furthermore, the results of in vivo experiments suggested that knockdown of HOTAIR expression increased the number of TH-positive cells and the number of α-synuclein-positive cells decreased while reducing the apoptosis rate among DA neurons. Our study confirmed that HOTAIR promotes PD progression by regulating miR-126-5p and RAB3IP in a ceRNA-dependent manner and further clarified how HOTAIR works in PD.

  1. Conflict of interest statement: The authors declare that they have no conflicts of interest regarding this work.

References

Ahmed, I., Liang, Y., Schools, S., Dawson, V.L., Dawson, T.M., and Savitt, J.M. (2012). Development and characterization of a new Parkinson’s disease model resulting from impaired autophagy. J. Neurosci. 32, 16503–16509.10.1523/JNEUROSCI.0209-12.2012Search in Google Scholar

Alvarez-Erviti, L., Seow, Y., Schapira, A.H., Rodriguez-Oroz, M.C., Obeso, J.A., and Cooper, J.M. (2013). Influence of microRNA deregulation on chaperone-mediated autophagy and alpha-synuclein pathology in Parkinson’s disease. Cell Death Dis. 4, e545.10.1038/cddis.2013.73Search in Google Scholar

Amagai, Y., Itoh, T., Fukuda, M., and Mizuno, K. (2015). Rabin8 suppresses autophagosome formation independently of its guanine nucleotide-exchange activity towards Rab8. J. Biochem. 158, 139–153.10.1093/jb/mvv032Search in Google Scholar

Barnett, R. (2016). Parkinson’s disease. Lancet 387, 217.10.1016/S0140-6736(16)00049-0Search in Google Scholar

Carrieri, C., Forrest, A.R., Santoro, C., Persichetti, F., Carninci, P., Zucchelli, S., and Gustincich, S. (2015). Expression analysis of the long non-coding RNA antisense to Uchl1 (AS Uchl1) during dopaminergic cells’ differentiation in vitro and in neurochemical models of Parkinson’s disease. Front. Cell Neurosci. 9, 114.10.3389/fncel.2015.00114Search in Google Scholar

Dauer, W. and Przedborski, S. (2003). Parkinson’s disease: mechanisms and models. Neuron 39, 889–909.10.1016/S0896-6273(03)00568-3Search in Google Scholar

de Bruijn, D.R., dos Santos, N.R., Kater-Baats, E., Thijssen, J., van den Berk, L., Stap, J., Balemans, M., Schepens, M., Merkx, G., and van Kessel, A.G. (2002). The cancer-related protein SSX2 interacts with the human homologue of a Ras-like GTPase interactor, RAB3IP, and a novel nuclear protein, SSX2IP. Genes Chromosomes Cancer 34, 285–298.10.1002/gcc.10073Search in Google Scholar PubMed

Fu, W.M., Zhu, X., Wang, W.M., Lu, Y.F., Hu, B.G., Wang, H., Liang, W.C., Wang, S.S., Ko, C.H., Waye, M.M., et al. (2015). Hotair mediates hepatocarcinogenesis through suppressing miRNA-218 expression and activating P14 and P16 signaling. J. Hepatol. 63, 886–895.10.1016/j.jhep.2015.05.016Search in Google Scholar PubMed

Gao, L., Li, C., Yang, R.Y., Lian, W.W., Fang, J.S., Pang, X.C., Qin, X.M., Liu, A.L., and Du, G.H. (2015). Ameliorative effects of baicalein in MPTP-induced mouse model of Parkinson’s disease: a microarray study. Pharmacol. Biochem. Behav. 133, 155–163.10.1016/j.pbb.2015.04.004Search in Google Scholar PubMed

Gui, Y., Liu, H., Zhang, L., Lv, W., and Hu, X. (2015). Altered microRNA profiles in cerebrospinal fluid exosome in Parkinson disease and Alzheimer disease. Oncotarget 6, 37043–37053.10.18632/oncotarget.6158Search in Google Scholar PubMed PubMed Central

Gupta, R.A., Shah, N., Wang, K.C., Kim, J., Horlings, H.M., Wong, D.J., Tsai, M.C., Hung, T., Argani, P., Rinn, J.L., et al. (2010). Long non-coding RNA HOTAIR reprograms chromatin state to promote cancer metastasis. Nature 464, 1071–1076.10.1038/nature08975Search in Google Scholar PubMed PubMed Central

He, J., Wu, K., Guo, C., Zhou, J.K., Pu, W., Deng, Y., Zuo, Y., Zhao, Y., Liu, L., Wei, Y.Q., et al. (2018). Long non-coding RNA AFAP1-AS1 plays an oncogenic role in promoting cell migration in non-small cell lung cancer. Cell Mol. Life Sci. 75, 4667–4681.10.1007/s00018-018-2923-8Search in Google Scholar PubMed

Homma, Y. and Fukuda, M. (2016). Rabin8 regulates neurite outgrowth in both GEF activity-dependent and -independent manners. Mol. Biol. Cell. 27, 2107–2118.10.1091/mbc.E16-02-0091Search in Google Scholar PubMed PubMed Central

Hossein-Nezhad, A., Fatemi, R.P., Ahmad, R., Peskind, E.R., Zabetian, C.P., Hu, S.C., Shi, M., Wahlestedt, C., Zhang, J., and Faghihi, M.A. (2016). Transcriptomic profiling of extracellular RNAs present in cerebrospinal fluid identifies differentially expressed transcripts in Parkinson’s disease. J. Parkinsons Dis. 6, 109–117.10.3233/JPD-150737Search in Google Scholar PubMed PubMed Central

Lan, Y.L., Zhou, J.J., Liu, J., Huo, X.K., Wang, Y.L., Liang, J.H., Zhao, J.C., Sun, C.P., Yu, Z.L., Fang, L.L., et al. (2018). Uncaria rhynchophylla ameliorates Parkinson’s disease by inhibiting HSP90 expression: insights from quantitative proteomics. Cell Physiol. Biochem. 47, 1453–1464.10.1159/000490837Search in Google Scholar PubMed

Lipovich, L., Tarca, A.L., Cai, J., Jia, H., Chugani, H.T., Sterner, K.N., Grossman, L.I., Uddin, M., Hof, P.R., Sherwood, C.C., et al. (2014). Developmental changes in the transcriptome of human cerebral cortex tissue: long noncoding RNA transcripts. Cereb Cortex. 24, 1451–1459.10.1093/cercor/bhs414Search in Google Scholar PubMed

Liu, X.H., Sun, M., Nie, F.Q., Ge, Y.B., Zhang, E.B., Yin, D.D., Kong, R., Xia, R., Lu, K.H., Li, J.H., et al. (2014). Lnc RNA HOTAIR functions as a competing endogenous RNA to regulate HER2 expression by sponging miR-331-3p in gastric cancer. Mol. Cancer 13, 92.10.1186/1476-4598-13-92Search in Google Scholar PubMed PubMed Central

Liu, S., Cui, B., Dai, Z.X., Shi, P.K., Wang, Z.H., and Guo, Y.Y. (2016). Long non-coding RNA HOTAIR promotes Parkinson’s disease induced by MPTP through up-regulating the expression of LRRK2. Curr. Neurovasc. Res. 13, 115–120.10.2174/1567202613666160316155228Search in Google Scholar PubMed

Liu, W., Zhang, Q., Zhang, J., Pan, W., Zhao, J., and Xu, Y. (2017). Long non-coding RNA MALAT1 contributes to cell apoptosis by sponging miR-124 in Parkinson disease. Cell Biosci. 7, 19.10.1186/s13578-017-0147-5Search in Google Scholar PubMed PubMed Central

Liu, L., Cui, S., Wan, T., Li, X., Tian, W., Zhang, R., Luo, L., and Shi, Y. (2018a). Long non-coding RNA HOTAIR acts as a competing endogenous RNA to promote glioma progression by sponging miR-126-5p. J. Cell Physiol. 233, 6822–6831.10.1002/jcp.26432Search in Google Scholar PubMed

Liu, Y., Zhang, J., Jiang, M., Cai, Q., Fang, J., and Jin, L. (2018b). MANF improves the MPP(+)/MPTP-induced Parkinson’s disease via improvement of mitochondrial function and inhibition of oxidative stress. Am. J. Transl. Res. 10, 1284–1294.Search in Google Scholar

Ma, M.Z., Li, C.X., Zhang, Y., Weng, M.Z., Zhang, M.D., Qin, Y.Y., Gong, W., and Quan, Z.W. (2014). Long non-coding RNA HOTAIR, a c-Myc activated driver of malignancy, negatively regulates miRNA-130a in gallbladder cancer. Mol. Cancer 13, 156.10.1186/1476-4598-13-156Search in Google Scholar

Martins, M., Rosa, A., Guedes, L.C., Fonseca, B.V., Gotovac, K., Violante, S., Mestre, T., Coelho, M., Rosa, M.M., Martin, E.R., et al. (2011). Convergence of miRNA expression profiling, alpha-synuclein interacton and GWAS in Parkinson’s disease. PLoS One 6, e25443.10.1371/journal.pone.0025443Search in Google Scholar

Marz, M., Ferracin, M., and Klein, C. (2015). MicroRNAs as biomarker of Parkinson disease? Small but mighty. Neurology 84, 636–638.10.1212/WNL.0000000000001275Search in Google Scholar

Modarresi, F., Faghihi, M.A., Lopez-Toledano, M.A., Fatemi, R.P., Magistri, M., Brothers, S.P., van der Brug, M.P., and Wahlestedt, C. (2012). Inhibition of natural antisense transcripts in vivo results in gene-specific transcriptional upregulation. Nat. Biotechnol. 30, 453–459.10.1038/nbt.2158Search in Google Scholar

Ozansoy, M. and Basak, A.N. (2013). The central theme of Parkinson’s disease: α-synuclein. Mol. Neurobiol. 47, 460–465.10.1007/s12035-012-8369-3Search in Google Scholar

Ren, H., Xu, Z., Guo, W., Deng, Z., and Yu, X. (2018). Rab3IP interacts with SSX2 and enhances the invasiveness of gastric cancer cells. Biochem, Biophys. Res. Commun. 503, 2563–2568.10.1016/j.bbrc.2018.07.016Search in Google Scholar

Riva, P., Ratti, A., and Venturin, M. (2016). The long non-coding RNAs in neurodegenerative diseases: novel mechanisms of pathogenesis. Curr. Alzheimer Res. 13, 1219–1231.10.2174/1567205013666160622112234Search in Google Scholar

Serra, P.A., Pluchino, S., Marchetti, B., Desole, M.S., and Miele, E. (2008). The MPTP mouse model: cues on DA release and neural stem cell restorative role. Parkinsonism Relat. Disord. 14(Suppl. 2), S189–S193.10.1016/j.parkreldis.2008.04.029Search in Google Scholar

Stoessl, A.J. (2014). Gene therapy for Parkinson’s disease: a step closer? Lancet 383, 1107–1109.10.1016/S0140-6736(13)62108-XSearch in Google Scholar

Thome, A.D., Harms, A.S., Volpicelli-Daley, L.A., and Standaert, D.G. (2016). microRNA-155 regulates Alpha-Synuclein-induced inflammatory responses in models of Parkinson disease. J. Neurosci. 36, 2383–2390.10.1523/JNEUROSCI.3900-15.2016Search in Google Scholar PubMed PubMed Central

Ultanir, S.K., Hertz, N.T., Li, G., Ge, W.P., Burlingame, A.L., Pleasure, S.J., Shokat, K.M., Jan, L.Y., and Jan, Y.N. (2012). Chemical genetic identification of NDR1/2 kinase substrates AAK1 and Rabin8 Uncovers their roles in dendrite arborization and spine development. Neuron 73, 1127–1142.10.1016/j.neuron.2012.01.019Search in Google Scholar PubMed PubMed Central

Wang, Y., Hou, J., He, D., Sun, M., Zhang, P., Yu, Y., and Chen, Y. (2016). The emerging function and mechanism of ceRNAs in cancer. Trends Genet. 32, 211–224.10.1016/j.tig.2016.02.001Search in Google Scholar PubMed PubMed Central

Wang, S., Zhang, X., Guo, Y., Rong, H., and Liu, T. (2017). The long noncoding RNA HOTAIR promotes Parkinson’s disease by upregulating LRRK2 expression. Oncotarget 8, 24449–24456.10.18632/oncotarget.15511Search in Google Scholar PubMed PubMed Central

Wang, C.L., Peng, J.P., and Chen, X.D. (2018). LncRNA-CIR promotes articular cartilage degeneration in osteoarthritis by regulating autophagy. Biochem. Biophys. Res. Commun. 505, 692–698.10.1016/j.bbrc.2018.09.163Search in Google Scholar PubMed

Wu, P., Zuo, X., Deng, H., Liu, X., Liu, L., and Ji, A. (2013). Roles of long noncoding RNAs in brain development, functional diversification and neurodegenerative diseases. Brain Res. Bull. 97, 69–80.10.1016/j.brainresbull.2013.06.001Search in Google Scholar PubMed

Xia, D., Sui, R., and Zhang, Z. (2018). Administration of resveratrol improved Parkinson’s disease-like phenotype by suppressing apoptosis of neurons via modulating the MALAT1/miR-129/SNCA signaling pathway. J. Cell Biochem. 120, 4942–4951.10.1002/jcb.27769Search in Google Scholar PubMed

Zhang, Q.S., Wang, Z.H., Zhang, J.L., Duan, Y.L., Li, G.F., and Zheng, D.L. (2016). Beta-asarone protects against MPTP-induced Parkinson’s disease via regulating long non-coding RNA MALAT1 and inhibiting alpha-synuclein protein expression. Biomed. Pharmacother. 83, 153–159.10.1016/j.biopha.2016.06.017Search in Google Scholar PubMed


Supplementary Material

The online version of this article offers supplementary material (https://doi.org/10.1515/hsz-2018-0431).


Received: 2018-11-14
Accepted: 2019-01-31
Published Online: 2019-07-19
Published in Print: 2019-08-27

© 2019 Walter de Gruyter GmbH, Berlin/Boston

Downloaded on 8.11.2025 from https://www.degruyterbrill.com/document/doi/10.1515/hsz-2018-0431/pdf
Scroll to top button