Co-expression gene modules involved in cisplatin-induced peripheral neuropathy according to sensitivity, status, and severity
Rui-Hao Zhou
Department of Pain Management, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorChan Chen
Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorSu-Han Jin
Department of Orthodontics, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
Search for more papers by this authorJun Li
Department of Pain Management, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorZi-Hao Xu
School of Public Health, Nanchang University, Nanchang, China
Search for more papers by this authorCorresponding Author
Ling Ye
Department of Pain Management, West China Hospital, Sichuan University, Chengdu, China
Correspondence
Ling Ye, Department of Pain Management, West China Hospital, Sichuan University, Guoxuexiang No. 37, Chengdu 610000, China.
Email: [email protected]
Jian-Guo Zhou, Department of Oncology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jian-Guo Zhou
Department of Oncology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany
Correspondence
Ling Ye, Department of Pain Management, West China Hospital, Sichuan University, Guoxuexiang No. 37, Chengdu 610000, China.
Email: [email protected]
Jian-Guo Zhou, Department of Oncology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
Email: [email protected]
Search for more papers by this authorRui-Hao Zhou
Department of Pain Management, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorChan Chen
Department of Anesthesiology and Translational Neuroscience Center, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorSu-Han Jin
Department of Orthodontics, Affiliated Stomatological Hospital of Zunyi Medical University, Zunyi, China
Search for more papers by this authorJun Li
Department of Pain Management, West China Hospital, Sichuan University, Chengdu, China
Search for more papers by this authorZi-Hao Xu
School of Public Health, Nanchang University, Nanchang, China
Search for more papers by this authorCorresponding Author
Ling Ye
Department of Pain Management, West China Hospital, Sichuan University, Chengdu, China
Correspondence
Ling Ye, Department of Pain Management, West China Hospital, Sichuan University, Guoxuexiang No. 37, Chengdu 610000, China.
Email: [email protected]
Jian-Guo Zhou, Department of Oncology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
Email: [email protected]
Search for more papers by this authorCorresponding Author
Jian-Guo Zhou
Department of Oncology, Affiliated Hospital of Zunyi Medical University, Zunyi, China
Department of Radiation Oncology, Universitätsklinikum Erlangen, Erlangen, Germany
Correspondence
Ling Ye, Department of Pain Management, West China Hospital, Sichuan University, Guoxuexiang No. 37, Chengdu 610000, China.
Email: [email protected]
Jian-Guo Zhou, Department of Oncology, Affiliated Hospital of Zunyi Medical University, Zunyi, China.
Email: [email protected]
Search for more papers by this authorRui-Hao Zhou and Chan Chen contributed equally to this study and should be considered as co-first authors.
Funding information: 1·3·5 project for disciplines of excellence-Clinical Research Incubation Project, West China Hospital, Sichuan University, Grant/Award Number: 2019HXFH069; Science and Technology Department of Sichuan Province, Grant/Award Number: 2020YJ0283
Abstract
Chemotherapy-induced peripheral neuropathy (CIPN) is among the most disabling and frustrating problems for cancer survivors. The neurotoxicity caused by cisplatin varies greatly among patients, and few predictors of appearance, duration of symptoms, susceptibility, or severity are available. A deeper understanding of the mechanisms underlying individual differences in status, severity, or sensitivity in response to cisplatin treatment is therefore required. By analyzing the GSE64174 gene expression profile and constructing a weighted gene co-expression network analysis (WGCNA) network, we screened gene modules and hub genes related to CIPN status, severity and sensitivity. We first identified the transcriptome profile of mouse dorsal root ganglion (DRG) samples and transformed their genes to human DRG counterparts. We then constructed WGCNA gene modules via optimal soft-threshold power-identification and module-preservation analysis. Comprehensive analysis and identification of module hub genes were performed via functional-enrichment analysis and significant common hub genes were identified, including “Cytoscape_cytoHubba,” “Cytoscape_MCODE,” and “Metascape_MCODE.” Brown, green, and blue modules were selected to represent CIPN sensitivity, status, and severity, respectively, via trait-module correlational analysis. Additionally, functional enrichment analysis results indicated that these three modules were associated with some crucial biological functions, such as neutrophil migration, chemokine-mediated signaling pathway, and PI3K-Akt signaling pathway. We then identified seven common hub genes via three methods, including CXCL10, CCL21, CCR2, CXCR4, TLR4, NPY1R, and GALR2, related to CIPN status, severity and sensitivity. Our results provide possible targets and mechanism insights into the development and progress of CIPN, which can guide further transformation and pre-clinical research.
CONFLICT OF INTEREST
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
Supporting Information
Filename | Description |
---|---|
jns12407-sup-0004-TableS1.xlsxExcel 2007 spreadsheet , 24.7 KB | Table S1 Functional enrichment analysis result of brown module. |
jns12407-sup-0005-TableS2.xlsxExcel 2007 spreadsheet , 38.5 KB | Table S2 Functional enrichment analysis result of green module. |
jns12407-sup-0006-TableS3.docxWord 2007 document , 12.5 KB | Table S3 Hub genes in the green module. |
jns12407-sup-0007-TableS4.xlsxExcel 2007 spreadsheet , 63.1 KB | Table S4 Functional enrichment analysis result of blue module. |
jns12407-sup-0008-TableS5.docxWord 2007 document , 12.6 KB | Table S5 Hub genes in the blue module. |
jns12407-sup-0001-FigS1.tifTIFF image, 1.4 MB | Figure S1 A heatmap of genes in selected module. A) Brown module/CIPN sensitivity, B) green module/ CIPN status, and C) blue module/CIPN severity. |
jns12407-sup-0002-FigS2.tifTIFF image, 1.9 MB | Figure S2 Comprehensive analysis and identification of green-module hub genes. A) Functional enrichment analysis; B) Construction of a PPI network; C) Identifying TOP 10 hub genes using the Cytoscape_cytoHubba plug-in; D) Identifying hub genes using the Cytoscape_MCODE plug-in; E) A PPI network constructed and hub gene identified by Metascape_MCODE plug-in; F) Identification of significant hub genes via Venn diagram: two significant common genes among “Cytoscape_MCODE,” “Metascape_MCODE,” and “Cytoscape_cytoHubba,” including CCR2 and CXCR4. |
jns12407-sup-0003-FigS3.tifTIFF image, 3.2 MB | Figure S3 Comprehensive analysis and identification of blue-module hub genes. A) Functional enrichment analysis; B) Construction of a PPI network; C) Identifying TOP 10 hub genes using the Cytoscape_cytoHubba plug-in; D) Identifying hub genes using the Cytoscape_MCODE plug-in; E) A PPI network constructed and hub gene identified by the Metascape_MCODE plug-in; F) Identification of significant hub genes via a Venn iagram. Ten significant common genes among “Cytoscape_MCODE,” and “Cytoscape_cytoHubba,” including LAMC1, LAMB1, LAMB2, IGFBP7, IGFBP5, VCAN, IGFBP3, LTBP1, NOTUM, and SERPIND1. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
REFERENCES
- 1Wolf S, Barton D, Kottschade L, Grothey A, Loprinzi C. Chemotherapy-induced peripheral neuropathy: prevention and treatment strategies. Eur J Cancer. 2008; 44(11): 1507-1515.
- 2Park SB, Goldstein D, Krishnan AV, et al. Chemotherapy-induced peripheral neurotoxicity: a critical analysis. CA Cancer J Clin. 2013; 63(6): 419-437.
- 3Cavaletti G, Alberti P, Argyriou AA, Lustberg M, Staff NP, Tamburin S. Chemotherapy-induced peripheral neurotoxicity: a multifaceted, still unsolved issue. J Peripher Nerv Syst. 2019; 24(2): S6-S12.
- 4Areti A, Yerra VG, Naidu VG, Kumar A. Oxidative stress and nerve damage: role in chemotherapy induced peripheral neuropathy. Redox Biol. 2014; 2: 289-295.
- 5Gu H, Wang C, Li J, et al. High mobility group box-1-toll-like receptor 4-phosphatidylinositol 3-kinase/protein kinase B-mediated generation of matrix metalloproteinase-9 in the dorsal root ganglion promotes chemotherapy-induced peripheral neuropathy. Int J Cancer. 2019; 146: 2810-2821.
- 6Storey DJ, Sakala M, CM ML, et al. Capecitabine combined with oxaliplatin (CapOx) in clinical practice: how significant is peripheral neuropathy? Ann Oncol. 2010; 21(8): 1657-1661.
- 7Staff NP, Cavaletti G, Islam B, Lustberg M, Psimaras D, Tamburin S. Platinum-induced peripheral neurotoxicity: from pathogenesis to treatment. J Peripher Nerv Syst. 2019; 24(2): S26-S39.
- 8McWhinney SR, Goldberg RM, McLeod HL. Platinum neurotoxicity pharmacogenetics. Mol Cancer Ther. 2009; 8(1): 10-16.
- 9Liu W, Ye J, Yan H. Investigation of key genes and pathways in inhibition of oxycodone on vincristine-induced microglia activation by using bioinformatics analysis. Dis Markers. 2019; 2019: 1746.
- 10Starobova H, Mueller A, Deuis JR, Carter DA, Vetter I. Inflammatory and neuropathic gene expression signatures of chemotherapy-induced neuropathy induced by vincristine, cisplatin, and oxaliplatin in C57BL/6J mice. J Pain. 2020; 21(1-2): 182-194.
- 11Calls A, Torres-Espin A, Navarro X, Yuste VJ, Udina E, Bruna J. Cisplatin-induced peripheral neuropathy is associated to neuronal senescence-like response. Neuro Oncol. 2020.
- 12Lessans S, Lassiter CB, Carozzi V, et al. Global transcriptomic profile of dorsal root ganglion and physiological correlates of cisplatin-induced peripheral neuropathy. Nurs Res. 2019; 68(2): 145-155.
- 13Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinformatics. 2008; 9: 559.
- 14Liu X, Hu A, Zhao J, Chen F. Identification of key gene modules in human osteosarcoma by co-expression analysis weighted gene co-expression network analysis (WGCNA). J Cell Biochem. 2017; 118(11): 3953-3959.
- 15Ray P, Torck A, Quigley L, et al. Comparative transcriptome profiling of the human and mouse dorsal root ganglia: an RNA-seq-based resource for pain and sensory neuroscience research. Pain. 2018; 159(7): 1325-1345.
- 16Zhang B, Horvath S. A general framework for weighted gene co-expression network analysis. Stat Appl Genet Mol Biol. 2005; 4: 17.
- 17Horvath S, Dong J. Geometric interpretation of gene coexpression network analysis. PLoS Comput Biol. 2008; 4(8):e1000117.
- 18Zhou Y, Zhou B, Pache L, et al. Metascape provides a biologist-oriented resource for the analysis of systems-level datasets. Nat Commun. 2019; 10(1): 1523.
- 19Szklarczyk D, L. Gable A, Lyon D, et al. STRING v11: protein-protein association networks with increased coverage, supporting functional discovery in genome-wide experimental datasets. Nucleic Acids Res. 2019; 47(1): D607-D613.
- 20Shannon P, Markiel A, Ozier O, et al. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res. 2003; 13(11): 2498-2504.
- 21Bader GD, Hogue CWV. An automated method for finding molecular complexes in large protein interaction networks. BMC Bioinformatics. 2003; 4(1): 2.
- 22Chin C-H, Chen S-H, Wu H-H, Ho C-W, Ko M-T, Lin C-Y. CytoHubba: identifying hub objects and sub-networks from complex interactome. BMC Syst Biol. 2014; 8: 11.
- 23Pathan M, Keerthikumar S, Chisanga D, et al. A novel community driven software for functional enrichment analysis of extracellular vesicles data. J Extracell Vesicles. 2017; 6(1): 1455.
- 24Dreszer TR, Karolchik D, Zweig AS, et al. The UCSC Genome Browser database: extensions and updates 2011. Nucleic Acids Res. 2012; 40: D918-D923.
- 25Piotrowska A, Rojewska E, Pawlik K, et al. Pharmacological blockade of CXCR3 by (±)-NBI-74330 reduces neuropathic pain and enhances opioid effectiveness - evidence from in vivo and in vitro studies. Mol Basis Dis. 2018; 1864(10): 3418-3437.
- 26Bäckryd E, Lind AL, Thulin M, Larsson A, Gerdle B, Gordh T. High levels of cerebrospinal fluid chemokines point to the presence of neuroinflammation in peripheral neuropathic pain: a cross-sectional study of 2 cohorts of patients compared with healthy controls. Pain. 2017; 158(12): 2487-2495.
- 27Liou J-T, Lee C-M, Day Y-J. The immune aspect in neuropathic pain: role of chemokines. Acta Anaesthesiol Taiwan. 2013; 51(3): 127-132.
- 28Zhou L, Ao L, Yan Y, et al. The therapeutic potential of chemokines in the treatment of chemotherapy- induced peripheral neuropathy. Curr Drug Targets. 2020; 21(3): 288-301.
- 29Illias AM, Gist AC, Zhang H, Kosturakis AK, Dougherty PM. Chemokine CCL2 and its receptor CCR2 in the dorsal root ganglion contribute to oxaliplatin-induced mechanical hypersensitivity. Pain. 2018; 159(7): 1308-1316.
- 30Zhou D-M, Zhuang Y, Chen W-J, Li W, Miao B. Effects of duloxetine on the toll-like receptor 4 signaling pathway in spinal dorsal horn in a rat model of diabetic neuropathic pain. Pain Med. 2017; 19(3): 580-588.
- 31Bruno K, Woller SA, Miller YI, et al. Targeting toll-like receptor-4 (TLR4)-an emerging therapeutic target for persistent pain states. Pain. 2018; 159(10): 1908-1915.
- 32Xu L, Liu Y, Sun Y, Li H, Mi W, Jiang Y. Analgesic effects of TLR4/NF-κB signaling pathway inhibition on chronic neuropathic pain in rats following chronic constriction injury of the sciatic nerve. Biomed Pharmacother. 2018; 107: 526-533.
- 33Li Y, Zhang H, Zhang H, Kosturakis AK, Jawad AB, Dougherty PM. Toll-like receptor 4 signaling contributes to paclitaxel-induced peripheral neuropathy. J Pain. 2014; 15(7): 712-725.
- 34Smith PA, Moran TD, Abdulla F, Tumber KK, Taylor BK. Spinal mechanisms of NPY analgesia. Peptides. 2007; 28(2): 464-474.
- 35Diaz-delCastillo M, Woldbye DPD, Heegaard AM. Neuropeptide Y and its involvement in chronic pain. Neuroscience. 2018; 387: 162-169.
- 36Nelson TS, Fu W, et al. Facilitation of neuropathic pain by the NPY Y1 receptor-expressing subpopulation of excitatory interneurons in the dorsal horn. Sci Rep. 2019; 9(1): 7248.
- 37Xu X-J, Hökfelt T, Wiesenfeld-Hallin Z. Galanin and spinal pain mechanisms: past, present, and future. Experientia Suppl. 2010; 102: 39-50.
- 38Metcalf CS, Smith MD, Klein BD, McDougle DR, Zhang L, Bulaj G. Preclinical analgesic and safety evaluation of the GalR2-preferring analog, NAX 810-2. Neurochem Res. 2017; 42(7): 1983-1994.
- 39Hökfelt T, Brumovsky P, Shi T, Pedrazzini T, Villar M. NPY and pain as seen from the histochemical side. Peptides. 2007; 28(2): 365-372.
- 40Diaz-delCastillo M, Christiansen SH, Appel CK, Falk S, Woldbye DPD, Heegaard AM. Neuropeptide Y is up-regulated and induces antinociception in cancer-induced bone pain. Neuroscience. 2018; 384: 111-119.
- 41Taylor BK, Fu W, Kuphal KE, et al. Inflammation enhances Y1 receptor signaling, neuropeptide Y-mediated inhibition of hyperalgesia, and substance P release from primary afferent neurons. Neuroscience. 2014; 256: 178-194.
- 42Liu HX, Brumovsky P, Schmidt R, et al. Receptor subtype-specific pronociceptive and analgesic actions of galanin in the spinal cord: selective actions via GalR1 and GalR2 receptors. Proc Natl Acad Sci USA. 2001; 98(17): 9960-9964.
- 43Xu XJ, Hökfelt T, Wiesenfeld-Hallin Z. Galanin and spinal pain mechanisms: where do we stand in 2008? Cell Mol Life Sci. 2008; 65(12): 1813-1819.