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General Research Article

Proteomic Analyses Reveal Functional Pathways and Potential Targets in Pediatric Hydrocephalus

Author(s): Yiwen Ju, Zhenling Wan, Qin Zhang, Si Li, Bingshu Wang, Jianmin Qiu, Shaojiang Zheng* and Shuo Gu*

Volume 23, Issue 5, 2023

Published on: 03 July, 2023

Page: [400 - 409] Pages: 10

DOI: 10.2174/1566523223666230613144056

Price: $65

Abstract

Introduction: Hydrocephalus is a common pediatric disorder of cerebral spinal fluid physiology resulting in abnormal expansion of the cerebral ventricles. However, the underlying molecular mechanisms remain unknown.

Methods: We performed proteomic analyses of cerebrospinal fluid (CSF) from 7 congenital hydrocephalus and 5 arachnoid cyst patients who underwent surgical treatment. Differentially expressed proteins (DEPs) were identified by label-free Mass Spectrometry followed by differential expression analysis. The GO and GSEA enrichment analysis was performed to explore the cancer hallmark pathways and immune-related pathways affected by DEPs. Then, network analysis was applied to reveal the location of DEPs in the human protein-protein interactions (PPIs) network. Potential drugs for hydrocephalus were identified based on drug-target interaction.

Results: We identified 148 up-regulated proteins and 82 down-regulated proteins, which are potential biomarkers for clinical diagnosis of hydrocephalus and arachnoid cyst. Functional enrichment analysis revealed that the DEPs were significantly enriched in the cancer hallmark pathways and immunerelated pathways. In addition, network analysis uncovered that DEPs were more likely to be located in the central regions of the human PPIs network, suggesting DEPs may be proteins that play important roles in human PPIs. Finally, we calculated the overlap of drug targets and the DEPs based on drugtarget interaction to identify the potential therapeutic drugs of hydrocephalus.

Conclusion: The comprehensive proteomic analyses provided valuable resources for investigating the molecular pathways in hydrocephalus, and uncovered potential biomarkers for clinical diagnosis and therapy.

Keywords: Proteomic, pediatric hydrocephalus, molecular pathways, DEPs, proteins, drugs.

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[1]
Kahle KT, Kulkarni AV, Limbrick DD Jr, Warf BC. Hydrocephalus in children. Lancet 2016; 387(10020): 788-99.
[http://dx.doi.org/10.1016/S0140-6736(15)60694-8] [PMID: 26256071]
[2]
Simon TD, Riva-Cambrin J, Srivastava R, Bratton SL, Dean JM, Kestle JR. Hospital care for children with hydrocephalus in the United States: Utilization, charges, comorbidities, and deaths. J Neurosurg Pediatr 2008; 1(2): 131-7.
[http://dx.doi.org/10.3171/PED/2008/1/2/131] [PMID: 18352782]
[3]
Tully HM, Dobyns WB. Infantile hydrocephalus: A review of epidemiology, classification and causes. Eur J Med Genet 2014; 57(8): 359-68.
[http://dx.doi.org/10.1016/j.ejmg.2014.06.002] [PMID: 24932902]
[4]
Gelabert-González M. (Intracranial arachnoid cysts). Rev Neurol 2004; 39(12): 1161-6.
[PMID: 15625636]
[5]
Westermaier T, Schweitzer T, Ernestus RI. Arachnoid Cysts. Adv Exp Med Biol 2012; 724: 37-50.
[http://dx.doi.org/10.1007/978-1-4614-0653-2_3] [PMID: 22411232]
[6]
Hall S, Smedley A, Sparrow O, et al. Natural history of Intracranial Arachnoid Cysts. World Neurosurg 2019; 126: e1315-20.
[http://dx.doi.org/10.1016/j.wneu.2019.03.087] [PMID: 30898748]
[7]
Mustansir F, Bashir S, Darbar A. Management of arachnoid cysts: A comprehensive review. Cureus 2018; 10(4): e2458.
[http://dx.doi.org/10.7759/cureus.2458] [PMID: 29888162]
[8]
Hochstetler A, Raskin J, Blazer-Yost BL. Hydrocephalus: Historical analysis and considerations for treatment. Eur J Med Res 2022; 27(1): 168.
[http://dx.doi.org/10.1186/s40001-022-00798-6] [PMID: 36050779]
[9]
Garcia-Bonilla M, McAllister J, Limbrick D. Genetics and molecular pathogenesis of human hydrocephalus. Neurol India 2021; 69(8) (Suppl.): 268.
[http://dx.doi.org/10.4103/0028-3886.332249] [PMID: 35102976]
[10]
McAllister JP II. Pathophysiology of congenital and neonatal hydrocephalus. Semin Fetal Neonatal Med 2012; 17(5): 285-94.
[http://dx.doi.org/10.1016/j.siny.2012.06.004] [PMID: 22800608]
[11]
Ren P, Wang J, Li L, et al. Identification of key genes involved in the recurrence of glioblastoma multiforme using weighted gene co-expression network analysis and differential expression analysis. Bioengineered 2021; 12(1): 3188-200.
[http://dx.doi.org/10.1080/21655979.2021.1943986] [PMID: 34238116]
[12]
Soneson C, Robinson MD. Bias, robustness and scalability in single-cell differential expression analysis. Nat Methods 2018; 15(4): 255-61.
[http://dx.doi.org/10.1038/nmeth.4612] [PMID: 29481549]
[13]
Hu JG, Fu SL, Zhang KH, et al. Differential gene expression in neural stem cells and oligodendrocyte precursor cells: A cDNA microarray analysis. J Neurosci Res 2004; 78(5): 637-46.
[http://dx.doi.org/10.1002/jnr.20317] [PMID: 15499592]
[14]
Hua XF, Wang XB, Liu FJ. Functional analysis of human cancer-associated genes and their association with the testes and epididymis. Oncol Lett 2013; 6(3): 811-6.
[http://dx.doi.org/10.3892/ol.2013.1450] [PMID: 24137416]
[15]
Yu G, Wang LG, Han Y, He QY. ClusterProfiler: An R package for comparing biological themes among gene clusters. OMICS 2012; 16(5): 284-7.
[http://dx.doi.org/10.1089/omi.2011.0118] [PMID: 22455463]
[16]
Kolberg L, Raudvere U, Kuzmin I, Vilo J, Peterson H. gprofiler2 -- an R package for gene list functional enrichment analysis and namespace conversion toolset g: Profiler. F1000 Res 2020; 9.
[17]
Jallo GI, Woo HH, Meshki C, Epstein FJ, Wisoff JH. Arachnoid cysts of the cerebellopontine angle: Diagnosis and surgery. Neurosurgery 1997; 40(1): 31-7.
[PMID: 8971821]
[18]
González GL, Ros-López B, Ibáñez-Botella G, Romero ML, Martin GA, Arráez-Sánchez MÁ. Neuroendoscopic treatment for hydrocephalus associated to midline arachnoid cysts in a series of nine pediatric patients. Minerva Pediatr 2017; 69(4): 256-63.
[PMID: 26041004]
[19]
Cincu R, Agrawal A, Eiras J. Intracranial arachnoid cysts: Current concepts and treatment alternatives. Clin Neurol Neurosurg 2007; 109(10): 837-43.
[http://dx.doi.org/10.1016/j.clineuro.2007.07.013] [PMID: 17764831]
[20]
Karimy JK, Reeves BC, Damisah E, et al. Inflammation in acquired hydrocephalus: Pathogenic mechanisms and therapeutic targets. Nat Rev Neurol 2020; 16(5): 285-96.
[http://dx.doi.org/10.1038/s41582-020-0321-y] [PMID: 32152460]
[21]
Pandey S, Yao PW, Qian Z, Ji T, Wang K, Gao L. Clinical characteristics of hydrocephalus following the treatment of pyogenic ventriculitis caused by multi/extensive Drug-Resistant Gram-Negative Bacilli, Acinetobacter Baumannii, and Klebsiella Pneumoniae. Front Surg 2022; 9: 854627.
[http://dx.doi.org/10.3389/fsurg.2022.854627] [PMID: 35592123]
[22]
Wang X, Zhou Y, Wang J, et al. SNX27 deletion causes hydrocephalus by impairing ependymal cell differentiation and ciliogenesis. J Neurosci 2016; 36(50): 12586-97.
[http://dx.doi.org/10.1523/JNEUROSCI.1620-16.2016] [PMID: 27974614]
[23]
Zhou Y, Hou Y, Shen J, Huang Y, Martin W, Cheng F. Network-based drug repurposing for novel coronavirus 2019-nCoV/SARS-CoV-2. Cell Discov 2020; 6(1): 14.
[http://dx.doi.org/10.1038/s41421-020-0153-3] [PMID: 32194980]
[24]
Lu Y, Yuan L, Chen X, Zhang A, Zhang P, Zou D. Systematic analysis and identification of unexpected interactions from the neuroprotein drug interactome in hydrocephalus pharmacological intervention. J Bioinform Comput Biol 2019; 17(1): 1950002.
[http://dx.doi.org/10.1142/S0219720019500021] [PMID: 30866733]
[25]
Tyanova S, Temu T, Cox J. The MaxQuant computational platform for mass spectrometry-based shotgun proteomics. Nat Protoc 2016; 11(12): 2301-19.
[http://dx.doi.org/10.1038/nprot.2016.136] [PMID: 27809316]
[26]
The Gene Ontology Consortium. Going forward. Nucleic Acids Res 2015; 43(D1): D1049-56.
[http://dx.doi.org/10.1093/nar/gku1179] [PMID: 25428369]
[27]
Subramanian A, Tamayo P, Mootha VK, et al. Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA 2005; 102(43): 15545-50.
[http://dx.doi.org/10.1073/pnas.0506580102] [PMID: 16199517]
[28]
Liberzon A, Birger C, Thorvaldsdóttir H, Ghandi M, Mesirov JP, Tamayo P. The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst 2015; 1(6): 417-25.
[http://dx.doi.org/10.1016/j.cels.2015.12.004] [PMID: 26771021]
[29]
Zou H, Pan T, Gao Y, et al. Pan-cancer assessment of mutational landscape in intrinsically disordered hotspots reveals potential driver genes. Nucleic Acids Res 2022; 50(9): e49.
[PMID: 35061901]
[30]
Wishart DS, Feunang YD, Guo AC, et al. DrugBank 5.0: A major update to the DrugBank database for 2018. Nucleic Acids Res 2018; 46(D1): D1074-82.
[http://dx.doi.org/10.1093/nar/gkx1037] [PMID: 29126136]
[31]
Shima Y, Copeland NG, Gilbert DJ, et al. Differential expression of the seven-pass transmembrane cadherin genesCelsr1-3 and distribution of the Celsr2 protein during mouse development. Dev Dyn 2002; 223(3): 321-32.
[http://dx.doi.org/10.1002/dvdy.10054] [PMID: 11891983]
[32]
Huber C, Cormier-Daire V. Ciliary disorder of the skeleton. Am J Med Genet C Semin Med Genet 2012; 160C(3): 165-74.
[http://dx.doi.org/10.1002/ajmg.c.31336] [PMID: 22791528]
[33]
Tissir F, Qu Y, Montcouquiol M, et al. Lack of cadherins Celsr2 and Celsr3 impairs ependymal ciliogenesis, leading to fatal hydrocephalus. Nat Neurosci 2010; 13(6): 700-7.
[http://dx.doi.org/10.1038/nn.2555] [PMID: 20473291]
[34]
Greig FH, Nixon GF. Phosphoprotein enriched in astrocytes (PEA)-15: A potential therapeutic target in multiple disease states. Pharmacol Ther 2014; 143(3): 265-74.
[http://dx.doi.org/10.1016/j.pharmthera.2014.03.006] [PMID: 24657708]
[35]
Xiao M, Li J, Liu Q, He X, Yang Z, Wang D. Expression and role of TRIM2 in human diseases. BioMed Res Int 2022; 2022: 1-14.
[http://dx.doi.org/10.1155/2022/9430509] [PMID: 36051486]
[36]
Li Y, Jiang T, Zhou W, et al. Pan-cancer characterization of immune-related lncRNAs identifies potential oncogenic biomarkers. Nat Commun 2020; 11(1): 1000.
[http://dx.doi.org/10.1038/s41467-020-14802-2] [PMID: 32081859]
[37]
Bhattacharya S, Dunn P, Thomas CG, et al. ImmPort, toward repurposing of open access immunological assay data for translational and clinical research. Sci Data 2018; 5(1): 180015.
[http://dx.doi.org/10.1038/sdata.2018.15] [PMID: 29485622]
[38]
Goh KI, Cusick ME, Valle D, Childs B, Vidal M, Barabási AL. The human disease network. Proc Natl Acad Sci 2007; 104(21): 8685-90.
[http://dx.doi.org/10.1073/pnas.0701361104] [PMID: 17502601]
[39]
Barrat A, Barthélemy M, Pastor-Satorras R, Vespignani A. The architecture of complex weighted networks. Proc Natl Acad Sci 2004; 101(11): 3747-52.
[http://dx.doi.org/10.1073/pnas.0400087101] [PMID: 15007165]
[40]
Linares TJ, Ros LB, Iglesias MS, Ibáñez BG, Ros SÁ, Arráez SMÁ. Neuroendoscopic treatment of arachnoid cysts in the paediatric population. Series results for 20 patients. Neurocirugia 2020; 31(4): 165-72.
[http://dx.doi.org/10.1016/j.neucie.2020.02.002] [PMID: 31883710]
[41]
Akgun B, Ozturk S, Hergunsel OB, Erol FS, Demir F. Endoscopic third ventriculostomy for obstructive hydrocephalus and ventriculocystostomy for intraventricular arachnoid cysts. Acta Med 2021; 64(1): 29-35.
[http://dx.doi.org/10.14712/18059694.2021.5] [PMID: 33855956]
[42]
Verkman AS, Tradtrantip L, Smith AJ, Yao X. Aquaporin water channels and hydrocephalus. Pediatr Neurosurg 2017; 52(6): 409-16.
[http://dx.doi.org/10.1159/000452168] [PMID: 27978530]
[43]
Ahluwalia P, Mondal AK, Bloomer C, et al. Identification and clinical validation of a novel 4 Gene-Signature with prognostic utility in colorectal cancer. Int J Mol Sci 2019; 20(15): 3818.
[http://dx.doi.org/10.3390/ijms20153818] [PMID: 31387239]
[44]
Hu X, Bao M, Huang J, Zhou L, Zheng S. Corrigendum: Identification and validation of novel biomarkers for diagnosis and prognosis of hepatocellular carcinoma. Front Oncol 2020; 10: 617539.
[http://dx.doi.org/10.3389/fonc.2020.617539] [PMID: 33330112]
[45]
Baharudin R, Tieng FYF, Lee LH, Ab Mutalib NS. Epigenetics of SFRP1: The dual roles in human cancers. Cancers 2020; 12(2): 445.
[http://dx.doi.org/10.3390/cancers12020445] [PMID: 32074995]
[46]
Bernemann C, Hülsewig C, Ruckert C, et al. Influence of secreted frizzled receptor protein 1 (SFRP1) on neoadjuvant chemotherapy in triple negative breast cancer does not rely on WNT signaling. Mol Cancer 2014; 13(1): 174.
[http://dx.doi.org/10.1186/1476-4598-13-174] [PMID: 25033833]
[47]
Jeong YJ, Jeong HY, Bong JG, Park SH, Oh HK. Low methylation levels of the SFRP1 gene are associated with the basal-like subtype of breast cancer. Oncol Rep 2013; 29(5): 1946-54.
[http://dx.doi.org/10.3892/or.2013.2335] [PMID: 23467623]
[48]
Lin H, Yang G, Ding B, et al. Secreted frizzled-related protein 1 overexpression in gastric cancer: Relationship with radiological findings of dual-energy spectral CT and PET-CT. Sci Rep 2017; 7(1): 42020.
[http://dx.doi.org/10.1038/srep42020] [PMID: 28169332]
[49]
Qu Y, Ray PS, Li J, et al. High levels of secreted frizzled-related protein 1 correlate with poor prognosis and promote tumourigenesis in gastric cancer. Eur J Cancer 2013; 49(17): 3718-28.
[50]
Saini S, Liu J, Yamamura S, et al. Functional significance of secreted Frizzled-related protein 1 in metastatic renal cell carcinomas. Cancer Res 2009; 69(17): 6815-22.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-1254] [PMID: 19723665]
[51]
van der Linden M, Meyaard L. Fine-tuning neutrophil activation: Strategies and consequences. Immunol Lett 2016; 178: 3-9.
[http://dx.doi.org/10.1016/j.imlet.2016.05.015] [PMID: 27262927]
[52]
Niyaz M, Khan MS, Mudassar S. Hedgehog signaling: An achilles’ heel in cancer. Transl Oncol 2019; 12(10): 1334-44.
[http://dx.doi.org/10.1016/j.tranon.2019.07.004] [PMID: 31352196]
[53]
Skoda AM, Simovic D, Karin V, Kardum V, Vranic S, Serman L. The role of the Hedgehog signaling pathway in cancer: A comprehensive review. Bosn J Basic Med Sci 2018; 18(1): 8-20.
[http://dx.doi.org/10.17305/bjbms.2018.2756] [PMID: 29274272]
[54]
Crescioli C. Chemokines and transplant outcome. Clin Biochem 2016; 49(4-5): 355-62.
[http://dx.doi.org/10.1016/j.clinbiochem.2015.07.026] [PMID: 26238260]

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