TDP-43 regulates cancer-associated microRNAs

Abstract

Aberrant regulation of miRNA genes contributes to pathogenesis of a wide range of human diseases, including cancer. The TAR DNA binding protein 43 (TDP-43), a RNA/DNA binding protein associated with neurodegeneration, is involved in miRNA biogenesis. Here, we systematically examined miRNAs regulated by TDP-43 using RNA-Seq coupled with an siRNA-mediated knockdown approach. TDP-43 knockdown affected the expression of a number of miRNAs. In addition, TDP-43 down-regulation led to alterations in the patterns of different isoforms of miRNAs (isomiRs) and miRNA arm selection, suggesting a previously unknown role of TDP-43 in miRNA processing. A number of TDP-43 associated miRNAs, and their candidate target genes, are associated with human cancers. Our data reveal highly complex roles of TDP-43 in regulating different miRNAs and their target genes. Our results suggest that TDP-43 may promote migration of lung cancer cells by regulating miR-423-3p. In contrast, TDP-43 increases miR-500a-3p expression and binds to the mature miR-500a-3p sequence. Reduced expression of miR-500a-3p is associated with poor survival of lung cancer patients, suggesting that TDP-43 may have a suppressive role in cancer by regulating miR-500a-3p. Cancer-associated genes LIF and PAPPA are possible targets of miR-500a-3p. Our work suggests that TDP-43-regulated miRNAs may play multifaceted roles in the pathogenesis of cancer.

Keywords

TDP-43 / miRNA / cancer / migration / prognosis

References

[1] Abu-Elneel K, Liu T, Gazzaniga FS, Nishimura Y, Wall DP, Geschwind DH, Lao K, Kosik KS (2008) Heterogeneous dysregulation of microRNAs across the autism spectrum. Neurogenetics 9:153–161

[2] Adams BD, Parsons C, Walker L, Zhang WC, Slack FJ (2017) Targeting noncoding RNAs in disease. J Clin Investig 127 (3):761–771

[3] Al-Shahrour F, Arbiza L, Dopazo H, Huerta-Cepas J, Mínguez P, Montaner D, Dopazo J(2007a) From genes to functional classes in the study of biological systems. BMC Bioinform 8:114

[4] Al-Shahrour F, Minguez P, Tarraga J, Medina I, Alloza E, Montaner D, Dopazo J (2007b) FatiGO+: a functional profiling tool for genomic data. Integration of functional annotation, regulatory motifs and interaction data with microarray experiments. Nucleic Acids Res 35:W91–W96

[5] Ambros V (2004) The functions of animal microRNAs. Nature 431:350–355

[6] Ambros V (2011) MicroRNAs and developmental timing. Curr Opin Genet Dev 21:511–517

[7] Audic S, Claverie JM (1997) The significance of digital gene expression profiles. Genome Res 7:986–995

[8] Ayala YM, De Conti L, Avendano-Vazquez SE, Dhir A, Romano M, D’Ambrogio A, Tollervey J, Ule J, Baralle M, Buratti E (2011) TDP-43 regulates its mRNA levels through a negative feedback loop. EMBO J 30:277–288

[9] Baccarini A, Chauhan H, Gardner Thomas J, Jayaprakash Anitha D, Sachidanandam R, Brown Brian D (2011) Kinetic analysis reveals the fate of a micrornA following target regulation in mammalian cells. Curr Biol 21:369–376

[10] Baker RG, Hsu CJ, Lee D, Jordan MS, Maltzman JS, Hammer DA, Baumgart T, Koretzky GA (2009) The adapter protein SLP-76 mediates “outside-in” integrin signaling and function in T cells. Mol Cell Biol 29:5578–5589

[11] Bao W, Kojima KK, Kohany O (2015) Repbase update, a database of repetitive elements in eukaryotic genomes. Mob DNA 6:11

[12] Baralle M, Buratti E, Baralle FE (2013) The role of TDP-43 in the pathogenesis of ALS and FTLD. BiochemSoc Trans 41:1536–1540

[13] Bartel DP (2009) MicroRNAs: target recognition and regulatory functions. Cell 136:215–233

[14] Betel D, Koppal A, Agius P, Sander C, Leslie C (2010) Comprehensive modeling of microRNA targets predicts functional nonconserved and non-canonical sites. Genome Biol 11:R90

[15] Bland JM, Altman DG (2004) The logrank test. BMJ 328:1073

[16] Bracken CP, Scott HS, Goodall GJ (2016) A network-biology perspective of microRNA function and dysfunction in cancer. Nat Rev Genet . 17(12):719–732

[17] Buratti E, De Conti L, Stuani C, Romano M, Baralle M, Baralle F (2010) Nuclear factor TDP-43 can affect selected microRNA levels. FEBS J 277:2268–2281

[18] Buratti E, Romano M, Baralle FE (2013) TDP-43 high throughput screening analyses in neurodegeneration: advantages and pitfalls. Mol Cell Neurosci 56:465–474

[19] Calin GA, Croce CM (2006) MicroRNA signatures in human cancers. Nat Rev Cancer 6:857–866

[20] Campos-Melo D, Droppelmann CA, Volkening K, Strong MJ (2014) RNA-binding proteins as molecular links between cancer and neurodegeneration. Biogerontology 15:587–610

[21] Chan PP, Lowe TM (2009) GtRNAdb: adatabase of transfer RNA genes detected in genomic sequence. Nucleic Acids Res 37:D93–D97

[22] Chen Y, Song Y, Wang Z, Yue Z, Xu H, Xing C, Liu Z (2010) Altered expression of MiR-148a and MiR-152 in gastrointestinal cancers and its clinical significance. J Gastrointest Surg 14:1170–1179

[23] Collins FS, Barker AD (2007) Mapping the cancer genome. Sci Am 296:50–57

[24] Cox DR (1972) Regression models and lift-tables. J R Stat Soc Ser B 34:187–220 (Methodological)

[25] Crawford M, Batte K, Yu L, Wu X, Nuovo GJ, Marsh CB, Otterson GA, Nana-Sinkam SP (2009) MicroRNA 133B targets prosurvival molecules MCL-1 and BCL2L2 in lung cancer. Biochem Biophys Res Commun 388:483–489

[26] Cummins JM, He Y, Leary RJ, Pagliarini R, Diaz LA Jr, Sjoblom T, Barad O, Bentwich Z, Szafranska AE, Labourier E (2006) The colorectal microRNAome. Proc Natl Acad Sci USA 103:3687–3692

[27] Czech B, Hannon GJ (2011) Small RNA sorting: matchmaking for Argonautes. Nat Rev Genet 12:19–31

[28] Delfino KR, Serao NV, Southey BR, Rodriguez-Zas SL (2011) Therapy-, gender- and race-specific microRNA markers, target genes and networks related to glioblastoma recurrence and survival. Cancer Genom Proteom 8:173–183

[29] Dodt M, Roehr J, Ahmed R, Dieterich C (2012) FLEXBAR—flexible barcode and adapter processing for next-generation sequencing platforms. Biology 1:895–905

[30] Enright AJ, John B, Gaul U, Tuschl T, Sander C, Marks DS (2003) MicroRNA targets in Drosophila. Genome Biol 5:R1

[31] Esquela-Kerscher A, Slack FJ (2006) Oncomirs—microRNAs with a role in cancer. Nat Rev Cancer 6:259–269

[32] Fan Z, Chen X, Chen R (2014) Transcriptome-wide analysis of TDP-43 binding small RNAs identifies miR-NID1 (miR-8485), a novel miRNA that represses NRXN1 expression. Genomics 103:76–82

[33] Fang HY, Chen SB, Guo DJ, Pan SY, Yu ZL (2011) Proteomic identification of differentially expressed proteins in curcumintreated MCF-7 cells. Phytomedicine 18:697–703

[34] Fanini F, Vannini I, Amadori D, Fabbri M (2011) Clinical implications of microRNAs in lung cancer. Semin Oncol 38:776–780

[35] Fernandez-Valverde SL, Taft RJ, Mattick JS (2010) Dynamic isomiR regulation in Drosophila development. Rna 16:1881–1888

[36] Freischmidt A, Müller K, Ludolph AC, Weishaupt JH (2013) Systemic dysregulation of TDP-43 binding microRNAs in amyotrophic lateral sclerosis. Acta Neuropathol Commun 1(1):42

[37] Friedman RC, Farh KK, Burge CB, Bartel DP (2009) Most mammalian mRNAs are conserved targets of microRNAs. Genome Res 19:92–105

[38] Gangnon KT, Maxwell ES (2011) Elecrophoretic mobility shift assay for characterizing RNA-protein interaction. Methods Mol Biol 703:275–291

[39] Gascon E, Gao FB (2014) The emerging roles of microRNAs in the pathogenesis of frontotemporal dementia-amyotrophic lateral sclerosis (FTD-ALS) spectrum disorders. J Neurogenet 28(1–2):30–40

[40] Gregory RI, Yan KP, Amuthan G, Chendrimada T, Doratotaj B, Cooch N, Shiekhattar R (2004) The Microprocessor complex mediates the genesis of microRNAs. Nature 432:235–240

[41] Griffiths-Jones S, Hui JHL, Marco A, Ronshaugen M (2011) MicroRNA evolution by arm switching. EMBO Rep 12:172–177

[42] Guo L, Yang Q, Lu J, Li H, Ge Q, Gu W, Bai Y, Lu Z (2011) A comprehensive survey of miRNA repertoire and 3’ addition events in the placentas of patients with pre-eclampsia from high-throughput sequencing. PLoS ONE 6:e21072

[43] Hackenberg M, Rodriguez-Ezpeleta N, Aransay AM (2011) miRanalyzer: an update on the detection and analysis of microRNAs in high-throughput sequencing experiments. Nucleic Acids Res 39: W132–W138

[44] Hammerman PS, Lawrence MS, Voet D, Jing R, Cibulskis K, Sivachenko A, Stojanov P, McKenna A, Lander ES, Gabriel S (2012) Comprehensive genomic characterization of squamous cell lung cancers. Nature 489(7417):519

[45] Hu Z, Wu C, Shi Y, Guo H, Zhao X, Yin Z, Yang L, Dai J, Hu L, Tan W (2011) A genome-wide association study identifies two new lung cancer susceptibility loci at 13q12.12 and 22q12.2 in Han Chinese. Nat Genet 43:792–796

[46] Huang JF, Wang Y, Guo YJ, Sun SH (2010) Down-regulated microRNA-152 induces aberrant DNA methylation in Hepatitis B virus-related hepatocellular carcinoma by targeting DNA methyltransferase 1. Hepatology 52:60–70

[47] Humphreys DT, Hynes CJ, Patel HR, Wei GH, Cannon L, Fatkin D, Suter CM, Clancy JL, Preiss T (2012) Complexity of murine cardiomyocyte miRNA biogenesis, sequence variant expression and function. PLoS One 7:e30933

[48] Hurd PJ, Nelson CJ (2009) Advantages of next-generation sequencing versus the microarray in epigenetic research. Brief Funct Genom Proteom 8:174–183

[49] Jiang Q, Wang Y, Hao Y, Juan L, Teng M, Zhang X, Li M, Wang G, Liu Y (2009) miR2Disease: a manually curated database for microRNA deregulation in human disease. Nucleic Acids Res 37: D98–D104

[50] Jonas S, Izaurralde E (2015) Towards a molecular understanding of microRNA-mediated gene silencing. Nat Rev Genet . 16(7):421–433

[51] Kawahara Y, Mieda-Sato A (2012) TDP-43 promotes microRNA biogenesis as a component of the Drosha and Dicer complexes . Proc Natl Acad Sci USA 109:3347–3352

[52] Kertesz M, Iovino N, Unnerstall U, Gaul U, Segal E (2007) The role of site accessibility in microRNA target recognition. Nat Genet 39:1278–1284

[53] Khvorova A, Reynolds A, Jayasena SD (2003) Functional siRNAs and miRNAs exhibit strand bias. Cell 115:209–216

[54] Kocerha J, Kouri N, Baker M, Finch N, DeJesus-Hernandez M, Gonzalez J, Chidamparam K, Josephs KA, Boeve BF, Graff-Radford NR (2011) Altered microRNA expression in frontotemporal lobar degeneration with TDP-43 pathologycaused by progranulin mutations. BMC Genome 12:527

[55] Kong YW, Ferland-McCollough D, Jackson TJ, Bushell M (2012) microRNAs in cancer management. Lancet Oncol 13:e249–e258

[56] Kozomara A, Griffiths-Jones S (2011) miRBase: integrating micro-RNA annotation and deep-sequencing data. Nucleic Acids Res 39:D152–D157

[57] Kozomara A, Griffiths-Jones S (2014) miRBase: annotating high confidence microRNAs using deep sequencing data. Nucleic Acids Res 42:D68–D73

[58] Krzywinski M, Birol I, Jones SJM, Marra MA (2012) Hive plotsrational approach to visualizing networks. Brief Bioinform 13:627–644

[59] Kuo PH, Doudeva LG, Wang YT, Shen CKJ, Yuan HS (2009) Structural insights into TDP-43 in nucleic-acid binding and domain interactions. Nucleic Acids Res 37:1799–1808

[60] Lagier-Tourenne C, Polymenidou M, Cleveland DW (2010) TDP-43 and FUS/TLS: emerging roles in RNA processing and neurodegeneration. Hum Mol Genet 19(R1):R46–R64

[61] Landgraf P, Rusu M, Sheridan R, Sewer A, Iovino N, Aravin A, Pfeffer S, Rice A, Kamphorst AO, Landthaler M (2007) A mammalian microRNA expression atlas based on small RNA library sequencing. Cell 129:1401–1414

[62] Langmead B, Trapnell C, Pop M, Salzberg SL (2009) Ultrafast and memory-efficient alignment of short DNA sequences to the human genome. Genome Biol 10:R25

[63] Lee LW, Zhang S, Etheridge A, Ma L, Martin D, Galas D, Wang K (2010) Complexity of the microRNA repertoire revealed by nextgeneration sequencing. RNA 16:2170–2180

[64] Lee EB, Lee VM, Trojanowski JQ (2012) Gains or losses: molecular mechanisms of TDP43-mediated neurodegeneration. Nat Rev Neurosci 13:38–50

[65] Lestrade L, Weber MJ (2006) snoRNA-LBME-db, a comprehensive database of human H/ACA and C/D box snoRNAs. Nucleic Acids Res 34:D158–D162

[66] Li S-C, Liao Y-L, Ho M-R, Tsai K-W, Lai C-H, Lin W-C (2012a) miRNA arm selection and isomiR distribution in gastric cancer. BMC Genome 13:S13

[67] Li Z, Lu Y, Xu XL, Gao FB (2012b) The FTD/ALS associated RNA binding protein TDP-43 regulates the robustness of neuronal specification through microRNA-9a in Drosophila. Hum Mol Genet 22(2):218–225

[68] Li Y, Liang C, Wong K-C, Jin K, Zhang Z (2014) Inferring probabilistic miRNA–mRNA interaction signatures in cancers: a role-switch approach. Nucleic Acids Res 42(9):e76

[69] Lin J, Huang S, Wu S, Ding J, Zhao Y, Liang L, Tian Q, Zha R, Zhan R, He X (2011) MicroRNA-423 promotes cell growth and regulates G1/S transition by targeting p21Cip1/Waf1 in hepatocellular carcinoma. Carcinogenesis 32:1641–1647

[70] Liu N, Abe M, Sabin Leah R, Hendriks G-J, Naqvi Ammar S, Yu Z, Cherry S, Bonini Nancy M (2011) The exoribonuclease nibbler controls 3′ end processing of micrornas in drosophila. Curr Biol 21:1888–1893

[71] Love MI, Huber W, Anders S (2014) Moderated estimation of fold change and dispersion for RNA-seq data with DESeq2. Genome Biol 15:31

[72] Luciano DJ (2004) RNA editing of a miRNA precursor. Rna 10:1174–1177

[73] Ma L, Young J, Prabhala H, Pan E, Mestdagh P, Muth D, Teruya-Feldstein J, Reinhardt F, Onder TT, Valastyan S (2010) miR-9, a MYC/MYCN-activated microRNA, regulates E-cadherin and cancer metastasis. Nat Cell Biol 12:U247–U252

[74] Maciotta S, Meregalli M, Torrente Y (2013) The involvement of microRNAs in neurodegenerative diseases. Front Cell Neurosci 7:265

[75] Malone JH, Oliver B (2011) Microarrays, deep sequencing and the true measure of the transcriptome. BMC Biol 9:34

[76] Marti E, Pantano L, Banez-Coronel M, Llorens F, Minones-Moyano E, Porta S, Sumoy L, Ferrer I, Estivill X (2010) A myriad of miRNA variants in control and Huntington’s disease brain regions detected by massively parallel sequencing. Nucleic Acids Res 38:7219–7235

[77] Medina I, Carbonell J, Pulido L, Madeira SC, Goetz S, Conesa A, Tárraga J, Pascual-Montano A, Nogales-Cadenas R, Santoyo J (2010) Babelomics: an integrative platform for the analysis of transcriptomics, proteomics and genomic data with advanced functional profiling. Nucleic Acids Res 38:W210–W213

[78] Mituyama T, Yamada K, Hattori E, Okida H, Ono Y, Terai G, Yoshizawa A, Komori T, Asai K (2009) The Functional RNA Database 3.0: databases to support mining and annotation of functional RNAs. Nucleic Acids Research 37:D89–D92

[79] Moore MJ, Silver PA (2008) Global Analysis of mRNA splicing. RNA 14:197–203

[80] Morin RD, O’Connor MD, Griffith M, Kuchenbauer F, Delaney A, Prabhu AL, Zhao Y, McDonald H, Zeng T, Hirst M (2008) Application of massively parallel sequencing to microRNA profiling and discovery in human embryonic stem cells. Genome Res 18:610–621

[81] Mostovich LA, Prudnikova TY, Kondratov AG, Loginova D, Vavilov PV, Rykova VI, Sidorov SV, Pavlova TV, Kashuba VI, Zabarovsky ER (2011) Integrin alpha9 (ITGA9) expression and epigenetic silencing in human breast tumors. Cell Adhes Migr 5:395–401

[82] Nelson PT, Wang W-X, Rajeev BW (2008) MicroRNAs (miRNAs) in neurodegenerative diseases. Brain Pathol 18:130–138

[83] Noorbakhsh J, Lang AH, Mehta P (2013) Intrinsic noise of microRNA-regulated genes and the ceRNA hypothesis. PLoS ONE 8:e72676

[84] Orang AV, Safaralizadeh R, Kazemzadeh-Bavili M (2014) Mechanisms of miRNA-mediated gene regulation from common downregulation to mRNA-specific upregulation. I nt J Genom 2014:1–15

[85] Osella M, Bosia C, Corá D, Caselle M (2011) The role of incoherent MicroRNA-mediated feedforward loops in noise buffering. PLoS Comput Biol 7:e1001101

[86] Pan H, Hanada S, Zhao J, Mao L, Ma MZ (2012) Protein secretion is required for pregnancy-associated plasma protein-a to promote lung cancer growth in vivo. PLoS ONE 7:e48799

[87] Park YY, Kim SB, Han HD, Sohn BH, Kim JH, Liang J, Lu Y, Rodriguez-Aguayo C, Lopez-Berestein G, Mills GB, Sood AK, Lee JS (2013) Tat-activating regulatory DNA-binding protein regulates glycolysis in hepatocellular carcinoma by regulating the platelet isoform of phosphofructokinase through microRNA 520. Hepatology 58(1):182–191

[88] Parpart S, Wang XW (2013) MicroRNA regulation and its consequences in cancer. Curr Pathobiol Rep 1:71–79

[89] Peritz T, Zeng F, Kannanayakal TJ, Kilk K, Eiríksdóttir E, Langel U, Eberwine J (2006) Immunoprecipitation of mRNA-protein complexes. Nat Protoc 1:577–580

[90] Polymenidou M, Lagier-Tourenne C, Hutt KR, Huelga SC, Moran J, Liang TY, Ling SC, Sun E, Wancewicz E, Mazur C (2011) Long pre-mRNA depletion and RNA missplicing contribute to neuronal vulnerability from loss of TDP-43. Nat Neurosci 14(4):459–468

[91] Postel-Vinay S, Véron AS, Tirode F, Pierron G, Reynaud S, Kovar H, Oberlin O, Lapouble E, Ballet S, Lucchesi C (2012) Common variants near TARDBP and EGR2 are associated with susceptibility to Ewing sarcoma. Nat Genet 44:323–327

[92] Quast C, Pruesse E, Yilmaz P, Gerken J, Schweer T, Yarza P, Peplies J, Glockner FO (2012) The SILVA ribosomal RNA gene database project: improved data processing and web-based tools. Nucleic Acids Res 41:D590–D596

[93] Quinlan AR, Hall IM (2010) BEDTools: a flexible suite of utilities for comparing genomic features. Bioinformatics 26:841–842

[94] Ratti A, Buratti E (2016) Physiological functions and pathobiology of TDP-43 and FUS/TLS proteins. J Neurochem 138:95–111

[95] Ruby JG, Jan C, Player C, Axtell MJ, Lee W, Nusbaum C, Ge H, Bartel DP (2006) Large-scale sequencing reveals 21U-RNAs and additional microRNAs and endogenous siRNAs in C. elegans. Cell 127:1193–1207

[96] Schwarz DS, Hutvagner G, Du T, Xu Z, Aronin N, Zamore PD (2003) Asymmetry in the assembly of the RNAi enzyme complex. Cell 115:199–208

[97] Sephton CF, Cenik C, Kucukural A, Dammer EB, Cenik B, Han Y, Dewey CM, Roth FP, Herz J, Peng J (2011) Identification of neuronal RNA targets of TDP-43-containingribonucleoprotein complexes. J Biol Chem 286:1204–1215

[98] Skrzypski M, Dziadziuszko R, Jassem J (2011) MicroRNA in lung cancer diagnostics and treatment. Mutat Res 717:25–31

[99] Soneson C, Love MI, Robinson MD (2016) Differential analyses for RNA-seq: transcript-level estimates improve gene-level inferences. F1000Research.

[100] Srinivasan S, Patric IR, Somasundaram K (2011) A ten-microRNA expression signature predicts survival in glioblastoma. PLoS One 6:e17438

[101] Sriram G, Birge RB (2010) Emerging roles for Crk in human cancer. Genes Cancer 1:1132–1139

[102] Tan X, Qin W, Zhang L, Hang J, Li B, Zhang C, Wan J, Zhou F, Shao K, Sun Y (2011) A 5-microRNA signature for lung squamous cell carcinoma diagnosis and hsa-miR-31 for prognosis. Clin Cancer Res 17:6802–6811

[103] Tarca AL, Drăghici S, Khatri P, Hassan SS, Mittal P, Kim J-S, Kim CJ, Kusanovic JP, Romero R (2009) A novel signaling pathway impact analysis. Bioinformatic s 25:75–82 (Oxford, England)

[104] Teittinen KJ, Kärkkäinen P, Salonen J, Rönnholm G, Korkeamäki H, Vihinen M, Kalkkinen N, Lohi O (2012) Nucleolar proteins with altered expression in leukemic cell lines. Leukemia Res 36:232–236

[105] Tollervey JR, Curk T, Rogelj B, Briese M, Cereda M, Kayikci M, Konig J, Hortobagyi T, Nishimura AL, Zupunski V (2011) Characterizing the RNA targets and position-dependent splicing regulation by TDP-43. Nat Neurosci 14:452–458

[106] Tsuruta T, Kozaki K, Uesugi A, Furuta M, Hirasawa A, Imoto I, Susumu N, Aoki D, Inazawa J (2011) miR-152 is a tumor suppressor microRNA that is silenced by DNA hypermethylation in endometrial cancer. Cancer Res 71:6450–6462

[107] Ule J, Jensen K, Mele A, Darnell RB (2005) CLIP: A method for identifying protein-RNA interaction sites in living cells. Methods 37:376–386

[108] Verhaak RG, Hoadley KA, Purdom E, Wang V, Qi Y, Wilkerson MD, Miller CR, Ding L, Golub T, Mesirov JP (2010) Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1. Cancer Cell 17:98–110

[109] Woo HH, Laszlo CF, Greco S, Chambers SK (2012) Regulation of colony stimulating factor-1 expression and ovarian cancer cell behavior in vitro by miR-128 and miR-152. Mol Cancer 11:58

[110] Wysoczynski M, Miekus K, Jankowski K, Wanzeck J, Bertolone S, Janowska-Wieczorek A, Ratajczak J, Ratajczak MZ (2007) Leukemia inhibitory factor: a newly identified metastatic factor in rhabdomyosarcomas. Cancer Res 67:2131–2140

[111] Xiao S, Sanelli T, Dib S, Sheps D, Findlater J, Bilbao J, Keith J, Zinman L, Rogaeva E, Robertson J (2011) RNA targets of TDP-43 identified by UV-CLIP are deregulated in ALS. Mol and Cell Neurosci 47:167–180

[112] Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, Stephens RM, Okamoto A, Yokota J, Tanaka T (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9:189–198

[113] Yu J, Cao Q, Mehra R, Laxman B, Yu J, Tomlins SA, Creighton CJ, Dhanasekaran SM, Shen R, Chen G (2007) Integrative genomics analysis reveals silencing of β-adrenergic signaling by polycomb in prostate Cancer. Cancer Cell 12:419–431

[114] Zhang Z, Almeida S, Lu Y, Nishimura AL, Peng L, Sun D, Wu B, Karydas AM, Tartaglia MC, Fong JC (2013) Downregulation of microRNA-9 in iPSC-derived neurons of FTD/ALS patients with TDP-43 mutations. PLoS One 8:e76055

[115] Zhou X, Zhao F, Wang ZN, Song YX, Chang H, Chiang Y, Xu HM (2012) Altered expression of miR-152 and miR-148a in ovarian cancer is related to cell proliferation. Oncol Rep 27:447–454

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