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Identification of Key Genes and Pathways Associated with Neuropathic Pain in Uninjured Dorsal Root Ganglion by Using Bioinformatic Analysis

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Identification of Key Genes and Pathways Associated with Neuropathic Pain in Uninjured Dorsal Root Ganglion by Using Bioinformatic Analysis Journal name: Journal of Pain Research Article Designation: ORIGINAL RESEARCH Year: 2017 Volume: 10 Journal of Pain Research Dovepress Running head verso: Chen et al Running head recto: Key genes and pathways in uninjured dorsal root ganglion open access to scientific and medical research DOI: http://dx.doi.org/10.2147/JPR.S143431 Open Access Full Text Article ORIGINAL RESEARCH Identification of key genes and pathways associated with neuropathic pain in uninjured dorsal root ganglion by using bioinformatic analysis Chao-Jin Chen* Purpose: Neuropathic pain is a complex chronic condition occurring post-nervous system dam- De-Zhao Liu* age. The transcriptional reprogramming of injured dorsal root ganglia (DRGs) drives neuropathic Wei-Feng Yao pain. However, few comparative analyses using high-throughput platforms have investigated Yu Gu uninjured DRG in neuropathic pain, and potential interactions among differentially expressed Fei Huang genes (DEGs) and pathways were not taken into consideration. The aim of this study was to identify changes in genes and pathways associated with neuropathic pain in uninjured L4 DRG Zi-Qing Hei after L5 spinal nerve ligation (SNL) by using bioinformatic analysis. Xiang Li Materials and methods: The microarray profile GSE24982 was downloaded from the Gene Department of Anesthesiology, The Expression Omnibus database to identify DEGs between DRGs in SNL and sham rats. The Third Affiliated Hospital of Sun Yat- sen University, Guangzhou, People’s prioritization for these DEGs was performed using the Toppgene database followed by gene Republic of China ontology and pathway enrichment analyses. The relationships among DEGs from the protein *These authors contributed equally to interactive perspective were analyzed using protein–protein interaction (PPI) network and this work module analysis. Real-time polymerase chain reaction (PCR) and Western blotting were used to confirm the expression of DEGs in the rodent neuropathic pain model. Results: A total of 206 DEGs that might play a role in neuropathic pain were identified in L4 DRG, of which 75 were upregulated and 131 were downregulated. The upregulated DEGs were enriched in biological processes related to transcription regulation and molecular functions such as DNA binding, cell cycle, and the FoxO signaling pathway. Ctnnb1 protein had the highest connectivity degrees in the PPI network. The in vivo studies also validated that mRNA and protein levels of Ctnnb1 were upregulated in both L4 and L5 DRGs. Conclusion: This study provides insight into the functional gene sets and pathways associated with neuropathic pain in L4 uninjured DRG after L5 SNL, which might promote our understand- ing of the molecular mechanisms underlying the development of neuropathic pain. Keywords: spinal nerve ligation, neuropathic pain, uninjured afferent, bioinformatic analysis, microarray Introduction Neuropathic pain is a complex chronic condition usually resulting from damage or Correspondence: Xiang Li Department of Anesthesiology, The disease affecting the nervous system. Up to 10% of the general population suffers Third Affiliated Hospital of Sun Yat-sen from neuropathic pain.1 Current treatments might relieve no more than 50% of pain University, Number 600, Tianhe Road, 2,3 Guangzhou 510630, People’s Republic intensity for only 30%–40% of patients in clinical practice. Therefore, identifica- of China tion of new and efficacious therapeutics toward neuropathic pain represents a major Tel/fax +86 20 8525 3132 Email [email protected] unmet medical need. submit your manuscript | www.dovepress.com Journal of Pain Research 2017:10 2665–2674 2665 Dovepress © 2017 Chen et al. This work is published and licensed by Dove Medical Press Limited. The full terms of this license are available at https://www.dovepress.com/terms. php and incorporate the Creative Commons Attribution – Non Commercial (unported, v3.0) License (http://creativecommons.org/licenses/by-nc/3.0/). By accessing the work http://dx.doi.org/10.2147/JPR.S143431 you hereby accept the Terms. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. For permission for commercial use of this work, please see paragraphs 4.2 and 5 of our Terms (https://www.dovepress.com/terms.php). Chen et al Dovepress The transcriptional reprogramming of dorsal root ganglia Microarray data preprocessing and DEG (DRGs) following sensory nerve damage is considered to identification 4 drive neuropathic pain. In the common neuropathic pain Preprocessing for the cell intensity (CEL) files including models that involve an injury to one or more peripheral conversion into expression measures and background cor- nerves, the DRG in injured nerve exhibits abnormal gene rection, and quartile data normalization was performed using expression and protein products that may play a role in neuro- BRB-ArrayTools (version 4.5.1).13,14 The DEGs between SNL 5 pathic pain. However, accumulating evidence indicates that and sham samples were identified using the unpaired t-test. changes in multiple genes and cellular pathways in DRG in A fold change ≥2.0 and nominal significance level of 0.05 adjacent, uninjured areas may also contribute to the occur- were applied in the BRB-ArrayTools to identify the DEGs 6 rence and development of neuropathic pain. For example, between the SNL and sham rats. the expression of some G protein-coupled receptors and ion channel molecules was changed in uninjured L4 DRGs after Prioritization for the DEGs L5 spinal nerve ligation (SNL).7,8 In addition, some targets To evaluate whether the DEGs obtained in the GEO dataset such as glial cell-derived neurotrophic factor (GDNF) might analysis might play a role in neuropathic pain, the prioritization exert their analgesic effects by acting on the central termi- for these DEGs was performed using the Toppgene database nals of uninjured L4 DRG neurons instead of injured L5 (http://toppgene.cchmc.org) with the threshold of P<0.05. Top- DRG neurons in an L5 SNL model.9 Therefore, identifying pgene is an online tool used for identification and prioritization the change in key transcripts and their protein products in of novel disease candidate genes in the interactome.15 The set uninjured DRG likely to initiate and sustain neuropathic pain of training genes, which was obtained from the published lit- might provide new insights into the underlying mechanism erature to train the software, was mined and integrated from the and treatment of this disease. online database GeneCards (http://genecards.org) by searching In recent decades, gene expression profiling for neuro- for the keywords “neuropathic pain.”16 pathic pain has been performed using microarray technology, and hundreds of differentially expressed genes (DEGs) in different pathways, biological processes (BPs), or molecular Gene ontology and pathway enrichment functions (MFs) were identified.10 However, little comparative analyses analyses by high-throughput platforms have been performed To identify the prioritized DEGs obtained from the Toppgene on uninjured DRGs in neuropathic pain, and potential interac- database, the genes and their products were annotated using tions among DEGs and pathways were not taken into con- gene ontology (GO) annotation analysis, and the signaling sideration. Notably, microarray technology combined with pathways were enriched using the Kyoto Encyclopedia of bioinformatic analysis allows comprehensive analysis of the Genes and Genomes (KEGG) pathway analysis. GO term expression changes of genes in neuropathic pain and other and KEGG pathway analysis were performed using the Data- diseases such as cancer.10,11 We reanalyzed microarray data base for Annotation, Visualization, and Integrated Discovery (GSE24982) submitted by von Schack et al12 from the Gene (DAVID; http://david.abcc.ncifcrf.gov/summary.jsp) online 17,18 Expression Omnibus (GEO) database using bioinformatic database. P<0.05 was considered statistically significant. technologies to identify the overall gene expression and pathway alterations in uninjured DRG and provide a more Construction of protein–protein thorough insight into the pathological changes in neuropathic interaction (PPI) network and module pain at the molecular level. analysis To evaluate the relationships among prioritized DEGs from Materials and methods the protein interactive perspective, we used the Search Tool Microarray data for the Retrieval of Interacting Genes/Proteins (STRING; We downloaded the microarray profile GSE24982 from http://www.string-db.org) to construct and identify PPI infor- the GEO database (http://www.ncbi.nlm.nih.gov/geo/). The mation among these genes.19 There are 9,643,763 proteins microarray data were collected from the L4 DRGs in L5 SNL from 2,031 organisms in the current version of the STRING (N=5) or sham rats (N=5). The gene annotation platform was database. A combination of more than 0.4 was considered based on GPL1355 (Affymetrix Rat Genome 230 2.0 Array). the reliability threshold for PPI. The PPI network was then 2666 submit your manuscript | www.dovepress.com Journal of Pain Research 2017:10 Dovepress Dovepress Key genes and pathways in uninjured dorsal root ganglion constructed and visualized using the Cytoscape software. The paw. The evaluation of mechanical allodynia was carried out importance of a protein in the PPI network was determined by an experimenter who was blinded to the treatment group. by its connectivity degree, namely the
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