Identification of Differentially Expressed Mirnas and Mrnas in Vestibular Schwannoma by Integrated Analysis

Hindawi BioMed Research International Volume 2019, Article ID 7267816, 10 pages https://doi.org/10.1155/2019/7267816

Research Article Identification of Differentially Expressed miRNAs and mRNAs in Vestibular Schwannoma by Integrated Analysis

Yanhua Lei, Ping Guo , Xiuguo Li, Yuanyuan Zhang, and Ting Du

Department of Otolaryngology, Jining No. 1 People’s Hospital, China

Correspondence should be addressed to Ping Guo; guoping [email protected]

Received 26 March 2019; Accepted 22 May 2019; Published 11 June 2019

Academic Editor: Alfredo Conti

Copyright © 2019 Yanhua Lei et al. Tis is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Background. Vestibular schwannoma (VS) is benign, slow-growing brain tumor that negatively impacts patient quality of life, which may cause even death. Tis study aimed to explore key genes and microRNAs (miRNAs) associated with VS. Methods. Te mRNA and miRNA expression profles of VS downloaded from Gene Expression Omnibus (GEO) database were included in this study to perform an integrated analysis. Te diferentially expressed mRNAs (DEmRNAs) and miRNAs (DEmiRNAs) were identifed. Ten, functional annotation and protein-protein interaction networks (PPI) of DEmRNAs were constructed. DEmiRNA-target DEmRNAs analysis and functional annotation of DEmiRNA-target DEmRNAs were performed. Results. A total of 2627 DEmRNAs (1194 upregulated and 1433 downregulated DEmRNAs) and 21 DEmiRNAs (12 upregulated and 9 downregulated DEmiRNAs) were identifed. ISG15, TLE1, and XPC were three hub proteins of VS-specifc PPI network. A total of 2970 DEmiRNAs-DEmRNAs pairs were obtained. Among which, hsa-miR-181a-5p, hsa-miR-106-5p, and hsa-miR-34a-5p were the top three DEmiRNAs that covered most DEmRNAs. Te functional annotation of DEmiRNA-target DEmRNAs revealed that the DEmiRNA-target DEmRNAs were signifcantly enriched in cGMP-PKG signaling pathway, adrenergic signaling in cardiomyocytes, and pathways in cancer. Conclusion. Te results of this present study may provide a comprehensive understanding for the roles of DEmRNAs and DEmiRNAs in the pathogenesis of VS and developing potential biomarkers of VS.

1. Introduction have been met with some success. Welling et al. identifed a number of deregulated genes in tumor tissue by using Vestibular schwannoma (VS), commonly termed acoustic cDNA microarray analysis of tissue samples from 1 vestibular neuromas, arise from the vestibular branch of the eighth nerve versus 3 cystic sporadic, 3 solid sporadic, and 1 NF2- cranial nerve and is benign, slow-growing brain tumors that associated vestibular schwannoma [5]. Caye-Tomasen´ et negatively impact patients’ quality of life, which may cause al. examined the gene expression in tissue samples from 3 hearing loss, tinnitus, facial palsy, and when large enough, human vestibular nerves versus 16 solid, sporadic vestibular brain stem compression, and even death [1, 2]. VS may appear schwannomas using a microarray chip and identifed more unilaterally but may also appear bilaterally when associated than 20,000 genes [6]. Aarhus et al. studied 25 VSs and 3 tibial with neurofbromatosis type 2 syndrome (NF2) [2]. To date, nerves (controls) with the ABI 1700 microarray platform and the identifcation of the NF2 gene is the most important obtained 1650 diferentially expressed genes [7]. However, fnding to our understanding of VS biology [3]. Current treat- the molecular events involved in the development of this ment modalities of VS are various, including observation, condition are not well understood. Tere is an urgent need to also known as wait-and-scan or watchful waiting, radiation investigate new therapeutic targets for VS and develop novel therapy (RT) and microsurgical resection (MS), based on treatment options. assorted factors, such as size at diagnosis, signifcant tumor MicroRNA (miRNA) is a new class of noncoding RNA growth on serial imaging, or patient symptoms [4]. molecules, which is short (∼21-23 nucleotides long), single- Recent eforts to defne the associated genes and molec- stranded RNA molecules and later shown to be a key ular pathways involved in tumorigenesis and expansion part of posttranscriptional regulatory mechanisms of gene 2 BioMed Research International expression in diverse organisms [8, 9]. MiRNAs broadly PPI network was then constructed by using Cytoscape participates in the regulation of protein translation and sofware (version 3.6.1, http://www.cytoscape.org). mRNAstabilityandarebelievedtoplaypivotalrolesinawide array of biological processes, including tumor development 2.5. DEmiRNA-Target DEmRNAs Analysis. As miRNAs tend [10–12]. As alterations in miRNA expression levels have been to decrease the expression of their target mRNAs, tar- linked with a variety of disease processes, focus on aberrant get genes from DEmRNAs that expressed inversely with expression in pathological states has increased [13]. that of miRNA were selected to subject to further inves- Tis present study performed an integrated analysis tigation [14]. Firstly, the putative targeted DEmRNAs of of miRNAs and mRNAs expression profles of VS down- DEmiRNAs were predicted by six bioinformatic algo- loaded from Gene Expression Omnibus (GEO) database. Te rithms (RNA22, miRanda, miRDB, miRWalk, PICTAR2, diferentially expressed mRNAs (DEmRNAs) and miRNAs and Targetscan). Ten, the confrmed targeted DEmRNAs (DEmiRNAs) were identifed. In addition, protein-protein of DEmiRNAs were obtained from miRWalk. Tirdly, the interaction (PPI) network of DEmRNAs was conducted. confrmed DEmiRNA-DEmRNA pairs were derived from DEmiRNA-target DEmRNAs analysis and functional anno- miRWalk and the DEmiRNA-DEmRNA pairs recorded by ≥ tation of DEmiRNA-target DEmRNAs were performed. In 4 algorithms. Based on the obtained DEmiRNA-DEmRNA doing so, we hope this study could represent a new avenue pairs, DEmiRNA-DEmRNA interaction networks between for understanding the pathogenesis and developing potential VS and normal controls were constructed by using Cytoscape biomarkers of VS. sofware (http://www.cytoscape.org/).

2. Materials and Methods 2.6. Functional Annotation of DEmiRNA Targets. To further research the biological function of the target DEmRNAs 2.1. Microarray Expression Profling in GEO. Te mRNA of DEmiRNAs, GO and KEGG pathway analysis were per- and miRNA expression profles of patients with VS were formed by using CPDB (http://cpdb.molgen.mpg.de/CPDB). downloaded from GEO database (http://www.ncbi.nlm FDR < 0.01 was set as the cut-of for signifcance. .nih.gov/geo). Te search strategy in the GEO datasets was as follows: (1) selected datasets should be mRNA/miRNA 3. Results transcriptome data of the whole genome; (2) these data were derived from tumor tissues and adjacent nontumor 3.1. DEmRNAs and DEmiRNAs between Patients with VS tissues of patients with VS; (3) datasets were standardized or and Normal Controls. Compared to normal controls, a total raw datasets. Tree datasets of mRNA expression profles, of 2627 DEmRNAs (1194 upregulated and 1433 downregu- including GSE108524, GSE56597, and GSE39645, and two lated DEmRNAs) and 21 DEmiRNAs (12 upregulated and 9 datasets of miRNA expression profles, including GSE43571 downregulated DEmiRNAs) were identifed. Te top 10 up- and GSE24390, were included in this study (Tables 1 and 2). and downregulated DEmRNAs and all DEmiRNAs between patients with VS and normal controls were displayed in Tables 2.2. Identifcation of DEmRNAs and DEmiRNAs in Patients 3 and 4, respectively. Hierarchical clustering analysis of top with VS Compared with Normal Controls. MetaMA, an R 100 up- and downregulated DEmRNAs and DEmiRNAs was package,isusedtocombinedatafrommultiplemicroar- displayed in Figure 1. ray datasets, and we obtained the individual P-values. Te Benjamini&Hochbergmethodwasusedtoobtainmultiple 3.2. Functional Annotation of DEmRNAs between Patients comparison correction false discovery rate (FDR). DEmR- with VS and Normal Controls. Anatomical structure devel- NAs and DEmiRNAs in VS compared to normal controls opment (FDR = 1.30E-33), multicellular organism devel- were obtained with FDR < 0.05 and FDR < 0.01, respectively. opment (FDR = 1.67E-33), intrinsic component of plasma Hierarchical clustering analysis of DEmRNAs was conducted membrane (FDR = 8.06E-10) and RNA polymerase II tran- by using R package “pheatmap”. scription factor activity, and sequence-specifc DNA binding (FDR = 3.72E-23) were signifcantly enriched GO terms in 2.3. Functional Annotation of DEmRNAs between Patients VS (Figures 2(a)–2(c)). Neuroactive ligand-receptor interac- with VS and Normal Controls. Functional annotation, tion (FDR = 1.49E-10), calcium signaling pathway (FDR = including Gene Ontology (GO) function and Kyoto 0.000137054), and cGMP-PKG signaling pathway (FDR = Encyclopedia of Genes and Genomes (KEGG) pathway 0.000853812) were signifcantly enriched KEGG pathways in enrichment analyses of the DEmRNAs between patients VS (Figure 2(d)). with VS and normal controls, were performed by CPDB (http://cpdb.molgen.mpg.de/CPDB). FDR < 0.01 was set as 3.3. PPI Network Construction. Te VS-specifc PPI network the cut-of for signifcance. was consisted of 308 nodes and 310 edges. ISG15 (degree = 26), TLE1 (degree = 24), and XPC (degree = 16) were three 2.4. PPI Network Construction. Top 50 up- and down- hub proteins of VS-specifc PPI network (Figure 3). regulated DEmRNAs were scanned with the Biological General Repository for Interaction Datasets (BioGrid, 3.4. DEmiRNA-Target Interactions. Atotalof2970DEm- http://www.uniprot.org/database/DB-0184). In order to iRNAs-DEmRNAs pairs, including 2570 DEmiRNAs- further explore the biological functions of the DEmRNAs, DEmRNAs pairs which were predicted by ≥ 4 algorithms BioMed Research International 3

Table 1: List of mRNA study samples from GEO. GEO Samples Author Platform Year accession (N:P) GPL17586 [HTA-2 0] Afymetrix Human Transcriptome GSE108524 Zhao Fu 4:27 2018 Array 2.0 [transcript (gene) version] Miguel GPL10739 [HuGene-1 0-st] Afymetrix Human Gene 1.0 GSE56597 Torres- 9:30 2014 ST Array [probe set (exon) version] Martin Miguel GPL6244 [HuGene-1 0-st] Afymetrix Human Gene 1.0 GSE39645 Torres- 9:31 2013 ST Array [transcript (gene) version] Martin

Table 2: List of miRNA study samples from GEO.

GEO Author Platform Samples(N:P) Year accession Miguel GPL8786 [miRNA-1] Afymetrix Multispecies GSE43571 3:16 2014 Torres-Martin miRNA-1 Array GSE24390 Okay Saydam GPL7436 Wurdinger/Krichevsky miRNA array IV 4:20 2010

Table 3: Top 10 up- and downregulated DEmRNAs between Table 4: All DEmiRNAs between patients with VS and normal patientswithVSandnormalcontrols. controls.

Gene symbol ID FDR Regulation Symbol FDR Regulation LARP6 55323 0 down hsa-mir-340 0.000965 down PRICKLE1 144165 0 down hsa-mir-10b 0.000965 down RAI2 10742 0 down hsa-mir-625 0.002215 down G0S2 50486 0 down hsa-mir-182 0.002215 down AQP1 358 0 down hsa-mir-412 0.004423 down MEOX1 4222 0 down hsa-mir-183 0.004423 down FOXP2 93986 0 down hsa-mir-181a 0.00834 down SOBP 55084 0 down hsa-mir-206 0.008414 down SLC6A9 6536 0 down hsa-mir-126 0.009816 down TACR1 6869 0 down hsa-mir-34a 7.66E-09 up BTK 695 0 up hsa-mir-30a 0.000965 up NLGN4X 57502 0 up hsa-mir-9 0.000965 up ZMAT3 64393 0 up hsa-mir-21 0.000965 up ATF7IP2 80063 0 up hsa-mir-601 0.002215 up P2RY12 64805 0 up hsa-mir-184 0.002215 up MR1 3140 0 up hsa-mir-628 0.00404 up CHD7 55636 0 up hsa-mir-654 0.00404 up CHPF 79586 0 up hsa-mir-30c 0.008414 up SLC15A3 51296 0 up hsa-mir-106b 0.009057 up SLC46A3 283537 0 up hsa-mir-377 0.009057 up DEmRNAs, diferentially expressed mRNAs; FDR, false discovery rate. hsa-mir-22 0.009412 up DEmiRNAs, diferentially expressed miRNAs; FDR, false discovery rate. and 568 validated DEmiRNAs-DEmRNAs pairs derived from the miRWalk, were obtained (Figure 4). Among which, (FDR = 1.09E-25), anatomical structure development (FDR hsa-miR-181a-5p (degree = 186), hsa-miR-106-5p (degree = = 3.24E-24), plasma membrane part (FDR = 1.78E-08), and 175), and hsa-miR-34a-5p (degree = 161) were the top three RNA polymerase II transcription factor activity, sequence- DEmiRNAs that covered most DEmRNAs. specifc DNA binding (FDR = 5.25E-17) were signifcantly enriched GO terms in VS (Figures 5(a)–5(c)). According 3.5. Functional Annotation of DEmiRNA Targets. Based on totheKEGGpathwayenrichmentanalysis,theDEmiRNA- GO enrichment analysis, anatomical structure development target DEmRNAs were signifcantly enriched in cGMP-PKG 4 BioMed Research International

Dataset Dataset 4 Label GSE108524 G0S2 GSE56597 AVPR1A GSE39645 S1PR1 FOXP2 Label PAK3 2 TJP2 Control ZBTB7C Case EFHD1 SLITRK4 TBX3 MASP1 0 MYOCD TNFSF15 THRSP TACR1 HAS2 DCLK1 −2 SLC6A9 APLNR DDIT4L CCL21 FOXD1 EBF1 LARP6 PRICKLE1 RGS6 KIAA1671 SHISA3 FIBIN SHISA6 SH3BGRL2 RAI2 PCOLCE2 TNNT2 GUCY1A2 AQP1 TSHZ2 BDKRB2 SOX9 MEOX1 FOXS1 HOXA2 SFRP2 HSPB6 SOBP INHBA PAWR PDE1C ZMAT3 FCGBP PROS1 GFRA1 CHPF PDGFC GPR83 ZC4H2 SERTAD2 BEX1 UHMK1 SAMD9 ISG15 SLC15A3 TUBB2B STARD13 NLGN4X SCN9A SCN7A TLE1 RHOJ P2RY12 ATF7IP2 USP32 TSPYL4 IFIT2 MID1 CHD7 PPM1K ANKRD22 SPP1 SLC2A5 CXorf21 GPR65 MSR1 SLC46A3 BTK CSF1R RNASE6 C3AR1 MR1 TLR3 UNC93B1 DIRAS2 SHMT1 XPC ZNF28 ZNF439 (a) Dataset Dataset GSE24390 Label 2 mir−206 GSE43571 mir−625 mir−628 Label 1 mir−183 Control mir−10b mir−126 Case mir−106b 0 mir−182 mir−654 mir−601 mir−377 −1 mir−412 mir−21 mir−22 mir−181a −2 mir−184 mir−30c mir−9 −3 mir−340 mir−30a mir−34a −4 (b)

Figure 1: Te heatmap of top 100 up- and downregulated DEmRNAs and DEmiRNAs between VS and normal controls. Row and column represented DEmRNAs/DEmiRNAs and tissue samples, respectively. Te color scale represented the expression levels. BioMed Research International 5

tissue development transporter complex

system development transmembrane transporter complex

regulation of multicellular organismal process transcription factor complex

regulation of developmental process plasma membrane protein complex

positive regulation of metabolic process plasma membrane part

positive regulation of cellular process plasma membrane

multicellular organism development −log10(FDR) nuclear transcription factor complex −log10(FDR) 30 8 epithelium development 25 intrinsic component of plasma membrane 6 20 4 epithelial cell diferentiation 15 intermediate flament cytoskeleton

cellular developmental process intermediate flament

cell diferentiation integral component of plasma membrane

animal organ morphogenesis cornifed envelope

animal organ development connexin complex

anatomical structure morphogenesis cell periphery

anatomical structure development cation channel complex

0 250 500 750 1000 0 200 400 600 800 (a) (b)

transcriptional activator activity, RNA polymerase II transcription regulatory region sequence−specifc DNA binding transcriptional activator activity, RNA polymerase II proximal promoter sequence−specifc DNA binding transcription regulatory region DNA binding transcription factor activity, RNA polymerase II proximal promoter sequence−specifc DNA binding sequence−specifc DNA binding −log10(FDR) RNA polymerase II transcription factor activity, sequence−specifc DNA binding regulatory region nucleic acid binding 20 receptor regulator activity receptor ligand activity 15 peptide receptor activity 10 G−protein coupled peptide receptor activity double−stranded DNA binding DNA binding transcription factor activity DNA binding cytokine activity 0 100 200 300 400 (c)

Signaling pathways regulating pluripotency of stem cells

Renin secretion

Pathways in cancer

Neuroactive ligand−receptor interaction −log10(FDR) 8 Cytokine−cytokine receptor interaction 6 4

cGMP−PKG signaling pathway

cAMP signaling pathway

Calcium signaling pathway

Adrenergic signaling in cardiomyocytes

0 25 50 75 100 (d)

Figure 2: Signifcantly enriched GO terms and KEGG pathways of DEmRNAs between patient with VS and normal controls. (a). BP,biological process; (b). CC, cellular component; (c). MF, molecular function; (d) KEGG pathways. Te x-axis shows counts of DEmRNAs enriched in GOtermsorKEGGpathwaysandthey-axisshowsGOtermsorKEGGpathways.Tecolorscalerepresented-lgFDR. 6 BioMed Research International

MAPK8IP2 SPAG9 ERBB3 ERRFI1 CHCHD1 GSTM4 MASP2 ARL4D CCL18 SERPINB9 SNRPD3 SNRPB2 MYB PPM1K MASP1 FOXA1 SNRPC FOXB1 TLX2 RPS6KA6 SIX6 DSTN MSX2 FOXA3 EIF2S2 YBX1 RBM15B ATF2 RPLP1 TAGLN PROP1 IFIT5 IFIT3 ERCC2 RGS6 OMP GSK3B TCF3 IFIT2 GNB3 PNMA1 PABPC4 EEF1G MX1 TLE1 APH1A CCDC85B TSPYL4 SHISA3 RPL24 VCP BEX1 TBX20 ZBTB7A NF2 SIX2 KRTAP4-2 AQP1 KRTAP10-8 HOMER3 KRTAP10-7 UBAP2L ISG15 IL6ST SMAD3 ZNF439 EIF2AK2 SOX9 MYOCD PBX2 KRTAP10-1 ARID5B DDX17 BAG4 HLX HOXD13 MYH9 WDR55 FOXG1 RRAS2 CCNDBP1 PIK3CA BARHL1 HOXC13 STK38 LDHA ANXA5 WDR1 MAF NR2F1 KRTAP10-5 FBXO45 PPP2R2D TCF4 HOXB9 FAM120C CALD1ZNF281 MED12 PAWR THRSP UQCRFS1 ARL8B HIST2H2AB RPA4 FOXS1 HIST1H2AG POU2F1 SLC5A1 HIST1H2BA FOXC1 PFN1 BARX1 XPA TGFB1 LSM3 UBE2N MYO6 CHD1L MDM2 TP53 UBTD1 ISCA1

ZBTB42 RPA1 ZNF428 XPC PARK7 RBM18 CETN2 TMOD2 HSPB1 HIST1H2BO MID1IP1 MID1 ZMAT3 CLDN1 SRRM2 CETN3 SGTB SSTR3 PPP2R1A PSMA6 RAI2 HSPB8 TNNT2 TLR6 KBTBD7 RPS8 APP CKS1B ATM TNPO3 TJP2 APOB HSPB6 UBE2W ATPAF2 GFRA1 EBF1 VKORC1L1 SOCS3 CLDN2 BRI3BP S1PR1 LARP6 BTK MEOX1 CSF1R POU5F1 QRICH1 CBL SRPK1 MCM5 TP53RKT CMTM6 KIF1C MSR1 BRD7 IL17RA CDK6 TRAF6 LRRC4 GEMIN4 NKG7 CHD7 TUBB3 HTR1D RAP2A JAK1 PTPN14 OLIG1 TUBB2B P2RY12 KIAA1671 GNAI1 MAP1B NES ITGA4 GNA13 RPL13 SOX2 ATOH1 NUS1 DCLK1 NF1 SASS6 AMOTL2 PDS5A TLR3 APLNR GPRIN1 CLEC2D SIPA1L1 C2orf50 SPP1 DCP1A LMBR1 STARD13 PCGF5 WDFY1 PML CEP170 COMMD1 TBX3 PLEKHF2 TMEM164 TIAM1 HELZ NEU2 MPPED1HDAC3H DOLK PDGFRB CDC25C CMTM3 CC2D1B ACAD9 ZNF804A CDK8 TMEM126B KIF13B RAB3B MAPKAP1 HSPA12A RIPK1 SERPINB8 MARCKS PSEN1 ATP2B4 ATP2B3 KRT8 IGFBP5 FOXP2 SDCBP MAP1A ATP12A CRK TACR1 PDE1A PIN1 SNRNP27 ZNF524 FOXD1 RHOJ RNF144A RPIA USP32 SERPINB6 EFHD1 SYNGR2 PAK3 C3AR1 KRT18 PLAT SLC2A5 GPR50 PDGFC PDE1C ITSN1 TAC1 ZC4H2 FOXD3 PARD6B F2 MTNR1A MED4 SLC7A2 MFSD5 VPS35 GOT2 TRIM27 KLHL22 GSPT2 ZDHHC21 CHPF PTCH1 CKAP4SLC35F5S PSMA3 CCL21 SLC15A3 HOXA2 DDIT4L SKIL RCHY1 CALCOCO2 DMPK

Figure 3: VS-specifc PPI network. Te red and green ellipses represented proteins encoded by up- and downregulated DEmRNAs between VS and normal controls. Ellipses with black border were DEmRNAs derived from top 10 up- and downregulated DEmRNAs between VS and normal controls. signaling pathway (FDR = 7.54E-05), adrenergic signaling in demonstrated that ISG15 was diferentially expressed in dif- cardiomyocytes (FDR = 0.00029), and pathways in cancer ferent tumor cells and diferent cell lines from same histologic (FDR = 0.000433) (Figure 5(d)). origin [18]. Zhang et al. reported that the expression of ISG15 mRNA and protein was signifcantly higher in tumors 4. Discussion than in adjacent control tissues [19]. Reportedly, ISG15 and UBE2L6 were identifed as negative regulators of autophagy VS is a benign tumor originating from the nerve sheath of in esophageal cancer cells [20]. In this present study, ISG15 one of the vestibular nerves. It is the most common extra- was signifcantly upregulated and a hub gene in PPI network axial tumor in the posterior fossa of adults, comprising over in VS. It is surmised that ISG15 may involve in VS. 80% of tumors in the cerebellopontine angle (CPA) [15]. In TLE family member 1, transcriptional corepressor (TLE1), exhibits a well-characterized function in the regulation of thisstudy,weperformedanintegratedanalysisbasedonthe nervous system development [21]. In particular, TLE1 exhibits databases downloaded from GEO to obtain key mRNAs and antineurogenic activity in mammalian forebrain develop- miRNAs associated with VS. To the best of our knowledge, it ment [21]. TLE1 is involved in diverse signaling pathways isthefrsttimetoconductanintegratedanalysisonmiRNAs and has important roles in neurogenesis, sex determination, and mRNAs expression profles of VS. and segmentation during development [22]. Previous studies ISG15, a small molecular weight protein, whose expres- suggest TLE1 could be used as a diagnostic marker and is sion is induced by interferon, was frst identifed as an a possible therapeutic target in various malignancies. Yao ubiquitin-likemodifedproteinandwasnamedubiquitin et al. reported that TLE1 was overexpressed in human lung cross-reactive protein as its structure was similar to ubiquitin tumors and may play an important role in promoting lung [16]. ISG15 has been postulated that it may directly or tumorigenesis and then speculated it may be a putative lung- indirectly be involved in tumor development [17]. It was specifc oncogene [21]. Bakrin et al. suggested that TLE1 BioMed Research International 7

ECE1 IREB2 HUS1 MRPL49 C15orf40 CENPBD1 NUP205 CXorf56 SLU7 POFUT2 LRPAP1 C20orf194 CALU R3HDM2 NAT8L FDXACB1 SKA2 SYDE2 RAB35 KLHL9 DMPK RSAD2 THUMPD1 ZFP36 POP4 CD59 PLA2G4F GCSH RPS29 SEZ6L2 TRIM52 EIF2AK2 MRFAP1L1 PAPOLB ZBTB8OS MFNG DLAT SYT11 SLITRK5 XPC ZFP3 KIDINS220 WDR13 CLPTM1 FAM120C WDR55 HEATR1 ZNF394 CAMK1D ILDR2 ZNF518B TBXAS1 SURF6 MAPRE2 TMEM50B CHD1L ZNF174 NIPSNAP3B SRA1 ALKBH4 KIF1C SERPINH1 MCPH1 C16orf54 GLOD4 USP24 BTN2A1 IPP RANBP6 C9orf3 EFCAB2 COL4A4 CXCL11 ZNF254 KCNG3 EVI2A CALCOCO2 ALDH1L2 CCDC122 LRRC4 DSTN NCOA4 KRT8 KSR2 N4BP2L1 PPP1R1C RNASE13 CSGALNACT2 PSME4 TRIM71 ADRB3 LIX1L ZBTB38 SNX10 S1PR4 PPP1R3C TNFSF8 TCF19 TP53BP1 C1QTNF7 CD209 LEFTY2 MAK16 LRRC58 ANAPC1 TFB1M TMEM140 ZBTB8B MAVS ZNF367 PTPN12 DOK6 PRAF2 CCDC3 C15orf62 ZNF90 CNTN1 HDAC9 F2 CTXN3 ZNF74 PSAT1 TTC39C PROS1 SLCO1B3 FOSL2 SLC30A1 KCTD16 HRK RAB9B TRAF6 CHML EID2B TMEM30B TMEM41B TNFSF4 HELZ RNF152 EMILIN3 ZBTB3 INSC DTX3L ADAMTS2 CBLN4 SST TFPI RAX KLF2 FZD2 PDE12 SLC11A2 ERBB3 PELI2 CDKN2B PPP1R15B RABIF DEFB132 PDE6G ADAMTS1 SNX8 hsa-miR-340-3p MMP1 MAPK8IP2 MEOX1 PLEKHF2 CCR1 CSGALNACT1 CUBN IP6K1 BHLHE41 ATOH8 CD2BP2 DUSP9 CYP8B1 SOD3 SCN3A METTL7A SAMD5 FAM122A FBXL14 SLC22A23 JRKL ZNF516 THAP6 SLITRK1 HCN2 PITPNC1 ZNF138 FYTTD1 CAPN1 PCDHB11 ZNF80 SLC39A2 CDKN2AIPNL RHOJ MGA KCNJ13 FAM3C LITAF HOXD13 WNT9B MAGEL2 ZNF497 LHFPL4 MSR1 NAT1 MTM1 FGD4 IFIT5 CALML5 TRMT5 CTNNA3 KLF13 FLT4 SLC35C1 ZNF543 MTRF1L SMAD3 RHOU FBXO22 HSPA12A RGS8 FAM84A RHOQ SCN7A LRCH2 ITSN1 AAK1 SLC26A2 BAG1 HOXC13 CDCA4 SERPINB8 hsa-miR-10b-5p NTNG1 C9orf152 GNG4 SDCBP IRX2 RPL10 GLUL ITGA11 GJC1 SLC24A2 CELSR1 NLGN4X ITGB8 GGCT ZKSCAN3 ANKRD40 CGNL1 PSMD13 SFMBT2 ATF7IP2 SP3 SP7 GRAMD1B ZNF287 DCLRE1B MSH3 TRIAP1 MC2R SPRY1 SPTBN2 BCR RAB17 CSF2RA GJB2 ATF6 ITPRIPL2 CACNB4 BARX2 BLK VASH1 ZNF519 NF1 INTS6 TACC1 RTN4 MAN2A2 ADRA1A SPRY3 SLC35E4 ZNF827 PDHA2 THSD7A hsa-miR-182-5p P2RY12 HEPH PSEN1 hsa-miR-412-3p CLN8 CSRNP2 OXR1 TNRC18 MYSM1 ZDHHC15 SNX19 IL17RA FAM43B hsa-miR-377-5p SFRP2 GJA1 ZNF708 GPR83 TTC33 C11orf87GPRC5B FGF9 PTP4A2 API5 ABL2 LARP4 CAMK2D TRIB2 DLX3 ZDHHC22 FRYL TPPP PGM3 CDS2 ABHD2 MGAT4A ABCA2 ASCL1 C1orf61 KPRP ACTL6A C10orf25 XYLT1 KRTAP1-1 HOXB8RCC2 ARSI PRKAR1A MTUS1 ATM POU2F1 DR1 MN1 COL6A6 PRPF19 RPS6KA6 GP5 UNK ZNF91 SOX2 MARCKS MRPS14 PPARA CLASP1 LYST RIMS2 HOPX CACNG1 DENND1B HIPK2 SERPINB9 ICAM1 HIST1H3C SHANK3 RPL24 ARL13B IDS EIF4E TBXA2R UBE2H LRRC66 FAM155B BASP1 RCHY1 TMEM186 FUS YY1 TAOK1 STX2 ZNF154 RAD18 LZIC LCE2B LTA METTL7B KCNQ2 PMEPA1 MTHFR AMOTL2 DDR2 ACAN PRMT6 UBR7 IRAK3 TNRC6A VCPIP1TOR1AIP2 PCGF5 PURA SAMD9 KCNJ15 PDX1 CDSN C2orf50 THRSP HIST2H3D LPO HSPB6 IER3 SMUG1 LDHA CRX VAMP4 SCN9A MRFAP1 ODF1 HIST3H2BB FOXS1 ISLR HIST1H4B MYL12A TBC1D5 hsa-miR-126-5p SPATA13 TMEM127 KCTD12 WDR31 hsa-miR-10b-3p KRTAP10-11 NRG2 AIF1L CDKN1C CBL RPL37 XKR5 PDE10A ATP2B4 LARP6 PPARG UNC13A ARID5B MR1 CC2D1B UBE2W ZNF445 HOXC12 PHLDA2 RHBG NEDD4L SNX2 FBXO45 CLCN3 PHC3 C4orf46 BCL2L14 ATP2B3 LRP11 PLCXD1 P2RY2 ALX4 GAS1 TAP2 WNK3PPP1R9A BRWD1 CASK RDX SUV39H2 CSNK1A1 FOXA3 SCN3B UNC5B HIST3H3 PDE5A HS6ST3 USP10 LSAMPRASSF8 MAGEA10 PPP1R3B JAG1 PAPPA2 KALRN AXL LCOR BCAP29 XPO5 NRARP B3GNT7 RASGRF2 LRRC38 OAZ2 TJP2 BCL2 MEX3C TNFRSF10B hsa-miR-183-3p ZNF654 AKT3 EDN2 CXXC4 PRTG LHX1 SYNGR2 TAGLN PNMA3 UBXN10 GREM2 SPATA12 SNX12 MERTK LUZP1 PAIP1 TOPBP1 TNIK GDF11 FZD1 FBXO40 SCN4B PABPC5 OPN4 PRR23C HPSE PDPK1 DPYSL2 BBS9 EYA1 ADORA2Bhsa-miR-22-5p UBAP2L TP53RK MDM2 CREB5 ASXL2 NUFIP2 ZNF681 TMLHE S100A10 PHLDA1 VPS53 MYO6 TCF7L2ADCYAP1R1MASP1 ZBTB7C FAM172A LPIN2 NPY2R FAM118A EBF1 AKR1B10 NPTX1 APCDD1L KIAA0040 VASN TMEM132B IRS1 LRP12 CALD1 LY6K ZBED3 MPP3 hsa-miR-106b-3p EIF2S3 ZBTB7A GSK3B SPAG9 BAG4 GGCX GPR26 ESR1 THBD POU4F1 SCN5A UBQLN2MAP3K9 PAFAH1B2 PEX19 STRBP SOCS6 TLE1 COL19A1 CLDN2 SH3BGRL2KCNN3 C1orf115 SLC29A4 P2RX4 MAP3K13 SCD CXCL12CACNG8 CLDN1 MAP7D1 CRK NPAT ADRA2C ARL4C FGF18 PPP1R3D MYB RAB27B FGF23 TMEM164 OPRL1 PHKG2 PTPN14 SESTD1 CREM RAP1A NHLH2 H2AFJ DCAF11 ENPEP KCNA6 MUC1 TIAM1 SYT13 BAIAP3 KRTAP10-7 ADD2 MYO9B ZMAT3 TMED5 MEF2D GCNT1 TTC31 NDST3 GABRA2 KLF8 ZNF704 RNF144A PTK6 B3GALT5 PHLDA3 SAMD4B PHYH MYBL1 MED12L ZBTB44 TMOD2 ADAMTS5C1QTNF2 SLC5A1 STC1 GPR55 LELP1 P2RY13 IRS2 EXOC8 PPP1R3F CSRNP3 NEUROD4 IMPDH1 MBLAC1 hsa-miR-625-5p TGFBR3 IL6ST ANKRD44 CD4 ID1 WNT2 EYA4 hsa-miR-9-5p NUS1 ADAM12FOXN3 ZBTB39 BRWD3 PLA2G12A PRPF40A KDSR LARS ATRX PTGER2 PDE11A ZNF648 C17orf102hsa-miR-601hsa-miR-21-5p HIST1H2BA KATNAL1 ABCD4 ZDHHC21 ITGBL1 PTCH1 XK NXPH3 GNAS BICD1 CTTNBP2NL STARD13 KLF3 TUSC3 LRRN1 TCF21 REPS2 hsa-miR-377-3p CACNA1ELRRC55 SPOCK2ZCCHC2 VEZF1 TAL2 hsa-miR-206 SOX6 WFDC12 ST8SIA1 PEX5L PNMA5 hsa-miR-22-3p PDE2A TMEM19C1GALT1 GPR173 DCBLD2 TUSC1 PAK3 KCTD4 FUT2 RASD2 CPLX2 HIST1H2BB STK3 SECISBP2L CYP19A1 STAG2 ZNF148 NOX4 FGF5 CACNA2D1hsa-miR-30a-3p hsa-miR-628-3p SOX12 PRICKLE1SOX11 PIN1 MAP1A hsa-miR-181a-5p C8orf59 CCL13 GRPEL2 hsa-miR-21-3p ZNF628 CYS1 SPATA6 ATP1B2 TSPYL4 PLAG1 RBPJ ZNF28 GPR88 ACVRL1 RNF24 SETBP1 POU5F1 DPY19L4 B2M KCNE3 PPP1R12B PML FOXE3 FCRL5 KLHL31 ITPKC ZIC4 FGD6 EFNA1 hsa-miR-34a-5p TPBG MYO9A CCDC6 CCKBR RBL1 SIX4 TSHZ2 KIF2A BCL10 CDK6 SBNO1 ZSCAN21 DGKH DCLK1 PCDH7 PROX1 GRM5 RASGRF1 TP53 SCML2 IL1RL1 THPO CHRNA4 SHMT2 GPR153 hsa-miR-183-5p IL15 MKL2 SPTBN1 PRKCD OPRD1 GPR12 DLC1 hsa-miR-182-3p CBLL1 SPP1 PRPF4B TSHZ3 MAML1 ADAM23 RNASEH2C hsa-miR-126-3p SGTB PDE1C SOX7 ARX CALN1 IGFBP5 MECP2 SCN2B RIMBP2 TREML2 TAF5 USP51 WDR5B H3F3C RAP2A YAF2 TMEM86A BAZ2B SPON2 LYPD5 ELFN2 FUT5 ACTG1 TOR2A CDC25C FGF2 MEX3B ZC3H12B RHOV SLITRK4 C9orf170ZFAND5 NF2 FOXL1 CMTM4 COX11 MYF6 PLEKHA6 RUNX1T1 LRP6 SLC7A2 NAMPT CDADC1 ZNF709 RBM15B hsa-miR-340-5p TGFBRAP1 CNR1 PGK2 VWC2L PLEKHG4B FAM89A FOXP2 MARCKSL1 PLN VCP CHD9 UHMK1 YIPF6 RAB2B YTHDF2 ZXDA hsa-miR-628-5p PBX1 RAB3B SDR9C7HIST1H2BO TRAPPC10 SORL1 ACACA MYOCD PLCXD3 KCNA1 S1PR1 PLXNA2 ATF2 WNT4 INHBB UNC5C FLJ44635 HIST1H1A MID1 ENDOD1 THAP2 CCDC62 SLC45A4 SFTPB TAL1 KCNA4 JAK1 TCF4 KCNJ12 GSPT1 CFL2 ESM1 ANKRD50 MAF DAP APOL6 SLC31A2 ZNF395 IRF4 AQP1 SHISA6 PTPRS GFRA1 ZADH2 UROS SHISA2 SIAH3 FNBP1 ZNF460 UCK2 FAM83A FBXL20 ZNF501 RAB18 ARL6IP6 TMEM158 HIC1 FNIP2 DGKE CLIC5 LYRM2 SLC12A2ADAMTS12 LRRFIP1 LMBR1 PCDH10 DCTN5 SOCS3 NMUR1 SH3BGRL3 AK2 VGLL4 ZSCAN29 MYO1E ZNF514 ONECUT1 MYCN hsa-miR-654-3p SVOP TTC30A C16orf72 OTUD1 MAP1B SMCR8 TBX3 HMGA2 DHCR24 MPPED1 YDJC PEF1 TAF9B UBTD2 hsa-miR-30a-5p RASL10B HIST1H4A CHST2 MTR SGCD ZNF281 LPAR5 PABPC4 SLC46A3 CEP170 SEMA5A STS FSHB SLITRK3 CCL22 ABCG4 PPP3R2 C15orf53 VDAC2 PLEKHG3 PPARGC1B CNOT6L SRGAP1 LRAT ZFR2 MGST1 PDE1A hsa-miR-654-5pPLEKHA2 IGSF3 IP6K2 MLEC C6orf62 HTR2A SYNPO2 SLC6A9 PAWR KPNA4 FAM91A1 C6orf15 SGSM1 hsa-miR-184 SHISA3 ADRA1D hsa-miR-625-3p ZNF439 KIAA1671 GNAO1 DIRAS2 DDX17 SERTAD2 GREB1 hsa-miR-30c-5pBLOC1S3 HOXA13 GP9 COL9A3 UBE2N PIAS2 PTPN22 HES2 GALR1 SCAMP5 MARVELD1 MYO5A SNRPD3 EPM2AIP1 ABCG2 FBXL7 SCN1A DKK2 PLEKHF1 TNFSF15 TBP CHD7 GNAI1 TTPAL FOXG1 hsa-miR-34a-3p DIO3 ZNF605 PNMA1 CAPRIN2 WDYHV1 MAP7 HK1 N4BP3 CDC20 HERC2 DCAF8L1 MBOAT2 SORBS2 LSM3 ATF5 MMP2 PPP1R11 CLN5 DNAJC7 HIGD2A PDE3A NR5A2 TLX2 GYS1 ARID4A NET1 NOL4 SIX5 PRND ADRA2A RPRML LRRC28 PPIE GTF2H5 UCN2 BDKRB2 OSR1 ABHD15 KIF5A YPEL2 KRTAP19-3 CCDC121 FBP1 WDFY1 DUSP6 MTF1 MYH9 CLEC2D FBXO10 ISCA1 CD69 PRSS23 SLC38A1 SIPA1L1 KCNV2 MYL6 hsa-miR-106b-5p METTL8 NAIF1 BAMBIGPRC5A BEND4 DCUN1D1 SOX9 PROP1 SH3D19 ZNF544 NAT2 CD93 TIGD2 TRIM5 NPTXR EDNRA SSTR5 NXT1 RYR3 NCKAP5 DCAF4L2 STAC JPH2 MEF2A ZBTB6 KLHL36 DDX27 PFN1 KNTC1 ZNF770 GOT2 TNFSF9 DDIT4L PARD6B XIRP1 TNFSF14 SNAI1 RPP25 TMEM150A ZNF268 TNFRSF11B HOXA11 CREB1 BBS10 SMARCA1 DNMT3B RTP1 NUBP1 GJD2 CCDC142 TMEM138 PAM RPIA ZCCHC13 PTPRJ RAPGEF1 ZNF124 ADRB1 FZD7 CAV2 CLIC4 CXCR4 RNF41 ZNF22 ZNF440 CD34 GPR137C PDGFRB VDR PRRT2 STARD9 RAD51 SLC28A3 IER5 TGFBR2 FAT1 ATG2B BMP2 PARVA PPP2CB RIF1 PDP2 RPAP3 ACSF3 TERF1 BCAS4 SIAH2 HLX SARS FAM43A GLE1 GPRIN3 DNAJB8 CECR2 DOK1 RC3H2 ABRA PBX2 EREG ADM ADAMTSL3 SLC30A4 STX11 CD48 CETN3 SRPK1 CKAP4 PIGW GNA12 FUCA2 CCDC25 AKAP5 MYCT1 FZD9 IQCC MKRN3 ADM2 FOXD1 SAMD10 RHOG FOXC1 FJX1 DERL2 GLI2 PDS5A RASEF PDE4C KCNJ3 TRIT1 RBM34 TRIM27 SPTLC2 AQP11 ZNF345 TRIM3 USH1G ARHGAP29 KCNJ11 SOBP ANKS4B MMP3 IL23R RASD1 FOXL2 TMEM151B DTYMK TADA2B RPA1 MUC17 GPR157 IGDCC3 PITX1 ELN ZNF619 TSKU NEUROD1 HOXC6 NDRG3 ATP12A SIX1 NHLH1 NARS2 TNFRSF21 ICAM4 FOXA1 HMGA1 ZC4H2 SOX4 ZIM3 SORCS2 C6orf132 ERRFI1 DIRAS1 SLC18A3 CLDN3 KLHL22 PSPH PLAT C9orf40 NKX3-2 IGSF9B CIC YBX1 GUCA2B HHIPL1 THRAP3 TNFAIP8L3 MXRA5 SNX5 ZNF135 C21orf58 SYPL2 GPIHBP1 FOXQ1 STK38 ATOX1 DMD HCN4 KCNJ8 F2RL1 RNPS1 LRRN4CL BRCC3 AICDA HTR1F WNT3A ZNF773 FSCB CXCL6 MARVELD3 TPM4 OMG GPRIN1 BNIP3 FIBIN NRSN2 LENEP SSBP2 FAM84B LMO3 SNAP47 PBOV1 WDR1 HOXD11 GTPBP10 SKIL ZSWIM3 TYW3 OLIG1 TUBB3 BAHCC1 CALML3 NHLRC2 HAS2 SLC39A8 ZBTB7B KCNA7 RWDD2ARAB20 (a) (b)

Figure 4: DEmiRNAs-DEmRNAs interaction network. (a) Interaction network between upregulated DEmiRNAs and downregulated DEmRNAs. (b) Interaction network between downregulated DEmiRNAs and upregulated DEmRNAs. Te rhombic nodes and elliptical nodes indicate DEmiRNAs and DEmRNAs, respectively. Red and green color represent upregulation and downregulation, respectively.

immunohistochemistry for synovial sarcoma can be very use- and neuronal development [30]. Te diverse physiological ful to distinguish synovial sarcoma from histological mimics efects of galanin are mediated by at least three galanin [23]. Additionally, TLE1 defciency resulted in enhanced receptor subtypes, including GalR1, GalR2, and GalR3 tumor growth [24]. In this analysis, TLE1 was a hub gene in [30]. PPI network as well, which may imply the important role of Misawa et al. indicated that GALR1/2 methylation sta- TLE1 in VS. tus may serve as an important site-specifc biomarker for Prickle1 is important for the nervous system develop- prediction of clinical outcome in patients with head and ment, and believed to be an integral part of the planar cell neck squamous cell carcinoma [31]. In addition, accord- polarity (PCP) pathway [25]. Prickle1 has been shown to ing to the KEGG pathway enrichment analysis, GALR1 regulate neuron morphogenesis, including neuron migra- was enriched in neuroactive ligand-receptor interaction. tion and neurite growth in the mouse [25–27]. Yang et Tese fndings may show that GALR1 is associated with al. suggested that in mice, Prickle1 was part of a molecu- VS. lar mechanism that regulated facial branchiomotor neuron BasedontheobtainedDEmiRNAs-DEmRNAspairs, caudal migration and separated the facial branchiomotor they revealed that both PRICKLE1 and GALR1 are targets neuron and the olivocochlear eferents [25]. Prickle1 was of hsa-miR-30c-5p and hsa-miR-30a-5p, which imply the showed to be highly expressed in the spiral ganglion and key role of hsa-miR-30 in VS. Accordingly, we proposed a involved in regulating distal and central outgrowth of spiral hypothesis that hsa-miR-30 may involve in VS by regulating ganglion neuron neurites of the inner ear [28]. PRICKLE1 PRICKLE1 and GALR1. was detected to be one of top 10 downregulated DEmRNAs In conclusion, abundant DEmiRNAs and DEmRNAs in VS. In view of this, we speculated PRICKLE1 may impli- between VS and normal controls were identifed which may cate in the pathogenesis of VS by participating in neuron make a contribution for developing new diagnostic and morphogenesis. therapeutic strategies for VS and emphasized the importance Galanin is a multifunctional neuropeptide initially iden- of several mRNAs and miRNAs which may implicate in VS. tifed from the porcine intestine [29]. In mammals, galanin Tese fndings may provide new insight into understanding is widely distributed in the central nervous system and the mechanism of VS. Te exact function of these mRNAs peripheral tissues, where it is involved in the modulation of and miRNAs in VS need to be determined with further hormone and neurotransmitter release, cognitive functions, research. 8 BioMed Research International

system development voltage−gated sodium channel complex

regulation of multicellular organismal process transporter complex

regulation of developmental process transmembrane transporter complex

regulation of cellular metabolic process plasma membrane region

regulation of biological process plasma membrane protein complex

positive regulation of metabolic process plasma membrane part

positive regulation of developmental process −log10(FDR) plasma membrane −log10(FDR) 22.5 7 positive regulation of biological process nucleus 6 20.0 5 17.5 4 negative regulation of cellular process membrane−bounded organelle

negative regulation of biological process intrinsic component of plasma membrane

multicellular organism development intracellular part

cellular developmental process intracellular

cell diferentiation integral component of plasma membrane

anatomical structure morphogenesis cell periphery

anatomical structure development cation channel complex 0 250 500 750 0 250 500 750 1000 (a) (b)

voltage−gated ion channel activity transcriptional activator activity, RNA polymerase II transcription regulatory region sequence−specifc DNA binding transcriptional activator activity, RNA polymerase II proximal promoter sequence−specifc DNA binding transcription regulatory region DNA binding transcription factor activity, RNA polymerase II proximal promoter sequence−specifc DNA binding −log10(FDR) sequence−specifc DNA binding 16 RNA polymerase II transcription factor activity, sequence−specifc DNA binding 14 regulatory region nucleic acid binding 12 protein binding 10 organic cyclic compound binding 8 nucleic acid binding 6 heterocyclic compound binding double−stranded DNA binding DNA binding transcription factor activity DNA binding 0 200 400 600 800 (c)

Wnt signaling pathway

Signaling pathways regulating pluripotency of stem cells

Renin secretion

Pathways in cancer

Neuroactive ligand−receptor interaction

Insulin signaling pathway

Human papillomavirus infection −log10(FDR) 4.0 Gastric cancer 3.5 3.0 2.5 Cushing,s syndrome

cGMP−PKG signaling pathway

cAMP signaling pathway

Calcium signaling pathway

Breast cancer

Basal cell carcinoma

Adrenergic signaling in cardiomyocytes 0 20 40 60 (d)

Figure 5: Signifcantly enriched GO terms and KEGG pathways of DEmiRNA-target DEmRNAs. (a). BP,biological process; (b). CC, cellular component; (c). MF, molecular function; (d) KEGG pathways. Te x-axis shows counts of DEmRNAs enriched in GO terms or KEGG pathways and the y-axis shows GO terms or KEGG pathways. Te color scale represented -lg FDR. BioMed Research International 9

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