Identification of Potential Biomarkers in Neonatal Sepsis by Establishing a Competitive Endogenous RNA Network

Author(s): Ling Liu, Hong Wang, Xiaofei Zhang, Rui Chen*

Journal Name: Combinatorial Chemistry & High Throughput Screening
Accelerated Technologies for Biotechnology, Bioassays, Medicinal Chemistry and Natural Products Research

Volume 23 , Issue 5 , 2020


Become EABM
Become Reviewer
Call for Editor

Abstract:

Background: Neonatal sepsis is a serious and difficult-to-diagnose systemic infectious disease occurring during the neonatal period.

Objective: This study aimed to identify potential biomarkers of neonatal sepsis and explore its underlying mechanisms.

Methods: We downloaded the neonatal sepsis-related gene profile GSE25504 from the NCBI Gene Expression Omnibus (GEO) database. The differentially expressed RNAs (DERs) were screened and identified using LIMMA. Then, the functions of the DERs were evaluated using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses. Finally, a competing endogenous RNA (ceRNA) network was constructed and functional analyses were performed.

Results: The initial screening identified 444 differentially expressed (DE)-mRNAs and 45 DElncRNAs. GO analysis showed that these DE-mRNAs were involved in immune response, defense response, and positive regulation of immune system process. KEGG analysis showed that these DE-mRNAs were enriched in 30 activated pathways and 6 suppressed pathways, and those with the highest scores were the IL-17 signaling pathway and ribosome. Next, 722 miRNAs associated with the identified lncRNAs were predicted using miRWalk. A ceRNA network was constructed that included 6 lncRNAs, 11 mRNAs, and 55 miRNAs. In this network, HCP5, LINC00638, XIST and TP53TG1 were hub nodes. Functional analysis of this network identified some essential immune functions, hematopoietic functions, osteoclast differentiation, and primary immunodeficiency as associated with neonatal sepsis.

Conclusion: HCP5, LINC00638, TP53TG1, ST20-AS1, and SERPINB9P1 may be potential biomarkers of neonatal sepsis and may be useful for rapid diagnosis; the biological process of the immune response was related to neonatal sepsis.

Keywords: Neonatal sepsis, differentially expressed RNAs, Gene Ontology (GO) terms, signaling pathways, ceRNA network, functional analysis.

[1]
Ganesan, P.; Shanmugam, P.; Sattar, S.B.A.; Shankar, S.L. Evaluation of IL-6, CRP and hs-CRP as early markers of neonatal sepsis. J. Clin. Diagn. Res., 2016, 10(5), DC13-DC17.
[http://dx.doi.org/10.7860/JCDR/2016/19214.7764] [PMID: 27437213]
[2]
Qiu, X.; Zhang, L.; Tong, Y.; Qu, Y.; Wang, H.; Mu, D. Interleukin-6 for early diagnosis of neonatal sepsis with premature rupture of the membranes: A meta-analysis. Medicine (Baltimore), 2018, 97(47) e13146
[http://dx.doi.org/10.1097/MD.0000000000013146] [PMID: 30461611]
[3]
Meng, Y.X.; Liu, Q.H.; Chen, D.H.; Meng, Y. Pathway cross-talk network analysis identifies critical pathways in neonatal sepsis. Comput. Biol. Chem., 2017, 68, 101-106.
[http://dx.doi.org/10.1016/j.compbiolchem.2017.02.007] [PMID: 28292731]
[4]
Liu, L.; Oza, S.; Hogan, D.; Perin, J.; Rudan, I.; Lawn, J.E.; Cousens, S.; Mathers, C.; Black, R.E. Global, regional, and national causes of child mortality in 2000-13, with projections to inform post-2015 priorities: an updated systematic analysis. Lancet, 2015, 385(9966), 430-440.
[http://dx.doi.org/10.1016/S0140-6736(14)61698-6] [PMID: 25280870]
[5]
Zea-Vera, A.; Ochoa, T.J. Challenges in the diagnosis and management of neonatal sepsis. J. Trop. Pediatr., 2015, 61(1), 1-13.
[http://dx.doi.org/10.1093/tropej/fmu079] [PMID: 25604489]
[6]
Shah, B.A.; Padbury, J.F. Neonatal sepsis: an old problem with new insights. Virulence, 2014, 5(1), 170-178.
[http://dx.doi.org/10.4161/viru.26906] [PMID: 24185532]
[7]
Benitz, W.E. Adjunct laboratory tests in the diagnosis of early-onset neonatal sepsis. Clin. Perinatol., 2010, 37(2), 421-438.
[http://dx.doi.org/10.1016/j.clp.2009.12.001] [PMID: 20569816]
[8]
Hofer, N.; Zacharias, E.; Müller, W.; Resch, B. An update on the use of C-reactive protein in early-onset neonatal sepsis: current insights and new tasks. Neonatology, 2012, 102(1), 25-36.
[http://dx.doi.org/10.1159/000336629] [PMID: 22507868]
[9]
Mehr, S.; Doyle, L.W. Cytokines as markers of bacterial sepsis in newborn infants: a review. Pediatr. Infect. Dis. J., 2000, 19(9), 879-887.
[http://dx.doi.org/10.1097/00006454-200009000-00014] [PMID: 11001114]
[10]
Cheng, Q.; Tang, L.; Wang, Y. Regulatory role of miRNA-26a in neonatal sepsis. Exp. Ther. Med., 2018, 16(6), 4836-4842.
[http://dx.doi.org/10.3892/etm.2018.6779] [PMID: 30542439]
[11]
Conte, F.; Fiscon, G.; Chiara, M.; Colombo, T.; Farina, L.; Paci, P. Role of the long non-coding RNA PVT1 in the dysregulation of the ceRNA-ceRNA network in human breast cancer. PLoS One, 2017, 12(2) e0171661
[http://dx.doi.org/10.1371/journal.pone.0171661] [PMID: 28187158]
[12]
Karreth, F.A.; Pandolfi, P.P. ceRNA cross-talk in cancer: when ce-bling rivalries go awry. Cancer Discov., 2013, 3(10), 1113-1121.
[http://dx.doi.org/10.1158/2159-8290.CD-13-0202] [PMID: 24072616]
[13]
Liz, J.; Esteller, M. lncRNAs and microRNAs with a role in cancer development. Biochim. Biophys. Acta, 2016, 1859(1), 169-176.
[http://dx.doi.org/10.1016/j.bbagrm.2015.06.015] [PMID: 26149773]
[14]
Cheng, Y.; Geng, L.; Wang, K.; Sun, J.; Xu, W.; Gong, S.; Zhu, Y. Long noncoding RNA expression signatures of colon cancer based on the ceRNA network and their prognostic value. Dis. Markers, 2019, 2019, 7636757
[http://dx.doi.org/10.1155/2019/7636757] [PMID: 30984308]
[15]
Liu, H.; Zhang, Z.; Wu, N.; Guo, H.; Zhang, H.; Fan, D.; Nie, Y.; Liu, Y. Integrative analysis of dysregulated lncRNA-associated ceRNA network reveals functional lncRNAs in gastric cancer. Genes (Basel), 2018, 9(6), 303.
[http://dx.doi.org/10.3390/genes9060303] [PMID: 29912172]
[16]
Wu, H.; Liu, J.; Li, W.; Liu, G.; Li, Z. LncRNA-HOTAIR promotes TNF-α production in cardiomyocytes of LPS-induced sepsis mice by activating NF-κB pathway. Biochem. Biophys. Res. Commun., 2016, 471(1), 240-246.
[http://dx.doi.org/10.1016/j.bbrc.2016.01.117] [PMID: 26806307]
[17]
Fang, Y.; Hu, J.; Wang, Z.; Zong, H.; Zhang, L.; Zhang, R.; Sun, L. LncRNA H19 functions as an Aquaporin 1 competitive endogenous RNA to regulate microRNA-874 expression in LPS sepsis. Biomed. Pharmacother., 2018, 105, 1183-1191.
[http://dx.doi.org/10.1016/j.biopha.2018.06.007] [PMID: 30021355]
[18]
Dickinson, P.; Smith, C.L.; Forster, T.; Craigon, M.; Ross, A.J.; Khondoker, M.R.; Ivens, A.; Lynn, D.J.; Orme, J.; Jackson, A.; Lacaze, P.; Flanagan, K.L.; Stenson, B.J.; Ghazal, P. Whole blood gene expression profiling of neonates with confirmed bacterial sepsis. Genom. Data, 2014, 3, 41-48.
[http://dx.doi.org/10.1016/j.gdata.2014.11.003] [PMID: 26484146]
[19]
Frankish, A.; Diekhans, M.; Ferreira, A-M.; Johnson, R.; Jungreis, I.; Loveland, J.; Mudge, J.M.; Sisu, C.; Wright, J.; Armstrong, J.; Barnes, I.; Berry, A.; Bignell, A.; Carbonell Sala, S.; Chrast, J.; Cunningham, F.; Di Domenico, T.; Donaldson, S.; Fiddes, I.T.; García Girón, C.; Gonzalez, J.M.; Grego, T.; Hardy, M.; Hourlier, T.; Hunt, T.; Izuogu, O.G.; Lagarde, J.; Martin, F.J.; Martínez, L.; Mohanan, S.; Muir, P.; Navarro, F.C.P.; Parker, A.; Pei, B.; Pozo, F.; Ruffier, M.; Schmitt, B.M.; Stapleton, E.; Suner, M-M.; Sycheva, I.; Uszczynska-Ratajczak, B.; Xu, J.; Yates, A.; Zerbino, D.; Zhang, Y.; Aken, B.; Choudhary, J.S.; Gerstein, M.; Guigó, R.; Hubbard, T.J.P.; Kellis, M.; Paten, B.; Reymond, A.; Tress, M.L.; Flicek, P. GENCODE reference annotation for the human and mouse genomes. Nucleic Acids Res., 2019, 47(D1), D766-D773.
[http://dx.doi.org/10.1093/nar/gky955] [PMID: 30357393]
[20]
Bradizza, C.M.; Stasiewicz, P.R.; Paas, N.D. Relapse to alcohol and drug use among individuals diagnosed with co-occurring mental health and substance use disorders: a review. Clin. Psychol. Rev., 2006, 26(2), 162-178.
[http://dx.doi.org/10.1016/j.cpr.2005.11.005] [PMID: 16406196]
[21]
Huang, W.; Sherman, B.T.; Lempicki, R.A. Systematic and integrative analysis of large gene lists using DAVID bioinformatics resources. Nat. Protoc., 2009, 4(1), 44-57.
[http://dx.doi.org/10.1038/nprot.2008.211] [PMID: 19131956]
[22]
Chiasson, P.M.; Pace, D.E.; Schlachta, C.M.; Mamazza, J.; Poulin, E.C. Minimally invasive surgery training in Canada: a survey of general surgery. Surg. Endosc., 2003, 17(3), 371-377.
[http://dx.doi.org/10.1007/s00464-002-8818-6] [PMID: 12436233]
[23]
Damian, D.; Gorfine, M. Statistical concerns about the GSEA procedure. Nat. Genet., 2004, 36(7), 663.
[http://dx.doi.org/10.1038/ng0704-663a] [PMID: 15226741]
[24]
Ogata, H.; Goto, S.; Sato, K.; Fujibuchi, W.; Bono, H.; Kanehisa, M. KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res., 1999, 27(1), 29-34.
[http://dx.doi.org/10.1093/nar/27.1.29] [PMID: 9847135]
[25]
Jason, M. Psych issues. JEMS, 2013, 38(3), 14.
[PMID: 23717912]
[26]
Shannon, P.; Markiel, A.; Ozier, O.; Baliga, N.S.; Wang, J.T.; Ramage, D.; Amin, N.; Schwikowski, B.; Ideker, T. Cytoscape: a software environment for integrated models of biomolecular interaction networks. Genome Res., 2003, 13(11), 2498-2504.
[http://dx.doi.org/10.1101/gr.1239303] [PMID: 14597658]
[27]
Li, J.H.; Liu, S.; Zhou, H.; Qu, L.H.; Yang, J.H. starBase v2.0: decoding miRNA-ceRNA, miRNA-ncRNA and protein-RNA interaction networks from large-scale CLIP-Seq data. Nucleic Acids Res., 2014, 42(Database issue), D92-D97.
[http://dx.doi.org/10.1093/nar/gkt1248] [PMID: 24297251]
[28]
Dweep, H.; Sticht, C.; Pandey, P.; Gretz, N. miRWalk--database: prediction of possible miRNA binding sites by “walking” the genes of three genomes. J. Biomed. Inform., 2011, 44(5), 839-847.
[http://dx.doi.org/10.1016/j.jbi.2011.05.002] [PMID: 21605702]
[29]
Lv, B.; Huang, J.; Yuan, H.; Yan, W.; Hu, G.; Wang, J. Tumor necrosis factor-α as a diagnostic marker for neonatal sepsis: a meta-analysis. ScientificWorldJournal, 2014, 2014(12) 471463
[http://dx.doi.org/10.1155/2014/471463] [PMID: 24672322]
[30]
Garg, A.V.; Amatya, N.; Chen, K.; Cruz, J.A.; Grover, P.; Whibley, N.; Conti, H.R.; Hernandez Mir, G.; Sirakova, T.; Childs, E.C.; Smithgall, T.E.; Biswas, P.S.; Kolls, J.K.; McGeachy, M.J.; Kolattukudy, P.E.; Gaffen, S.L. MCPIP1 endoribonuclease activity negatively regulates interleukin-17-mediated signaling and inflammation. Immunity, 2015, 43(3), 475-487.
[http://dx.doi.org/10.1016/j.immuni.2015.07.021] [PMID: 26320658]
[31]
Pan, B.; Shen, J.; Cao, J.; Zhou, Y.; Shang, L.; Jin, S.; Cao, S.; Che, D.; Liu, F.; Yu, Y. Interleukin-17 promotes angiogenesis by stimulating VEGF production of cancer cells via the STAT3/GIV signaling pathway in non-small-cell lung cancer. Sci. Rep., 2015, 5, 16053.
[http://dx.doi.org/10.1038/srep16053] [PMID: 26524953]
[32]
Song, X.; Qian, Y. IL-17 family cytokines mediated signaling in the pathogenesis of inflammatory diseases. Cell. Signal., 2013, 25(12), 2335-2347.
[http://dx.doi.org/10.1016/j.cellsig.2013.07.021] [PMID: 23917206]
[33]
Gelderblom, M.; Weymar, A.; Bernreuther, C.; Velden, J.; Arunachalam, P.; Steinbach, K.; Orthey, E.; Arumugam, T.V.; Leypoldt, F.; Simova, O.; Thom, V.; Friese, M.A.; Prinz, I.; Hölscher, C.; Glatzel, M.; Korn, T.; Gerloff, C.; Tolosa, E.; Magnus, T. Neutralization of the IL-17 axis diminishes neutrophil invasion and protects from ischemic stroke. Blood, 2012, 120(18), 3793-3802.
[http://dx.doi.org/10.1182/blood-2012-02-412726] [PMID: 22976954]
[34]
Lawrence, S.M.; Ruoss, J.L.; Wynn, J.L. IL-17 in neonatal health and disease. Am. J. Reprod. Immunol., 2018, 79(5) e12800
[http://dx.doi.org/10.1111/aji.12800] [PMID: 29243317]
[35]
He, S.; Li, X.; Li, R.; Fang, L.; Sun, L.; Wang, Y.; Wu, M. Annexin A2 Modulates ROS and Impacts Inflammatory Response via IL-17 Signaling in Polymicrobial Sepsis Mice. PLoS Pathog., 2016, 12(7) e1005743
[http://dx.doi.org/10.1371/journal.ppat.1005743] [PMID: 27389701]
[36]
Chen, J.; Zhao, D.; Meng, Q. Knockdown of HCP5 exerts tumor-suppressive functions by up-regulating tumor suppressor miR-128-3p in anaplastic thyroid cancer. Biomed. Pharmacother., 2019, 116, 108966
[http://dx.doi.org/10.1016/j.biopha.2019.108966] [PMID: 31102936]
[37]
Rajesh, D.; Nagraj, S.; Kumar, K.S.P.; Kutty, A.V.M.; Balakrishna, S. Evaluation of HCP5 and chemokine C receptor type 5 gene polymorphisms in Indian psoriatic patients. Indian J. Dermatol., 2019, 64(3), 182-186.
[http://dx.doi.org/10.4103/ijd.IJD_285_18] [PMID: 31148855]
[38]
Wang, L.; Luan, T.; Zhou, S.; Lin, J.; Yang, Y.; Liu, W.; Tong, X.; Jiang, W. LncRNA HCP5 promotes triple negative breast cancer progression as a ceRNA to regulate BIRC3 by sponging miR-219a-5p. Cancer Med., 2019, 8(9), 4389-4403.
[http://dx.doi.org/10.1002/cam4.2335] [PMID: 31215169]
[39]
Zhao, Q.; Fan, C. A novel risk score system for assessment of ovarian cancer based on co-expression network analysis and expression level of five lncRNAs. BMC Med. Genet., 2019, 20(1), 103.
[http://dx.doi.org/10.1186/s12881-019-0832-9] [PMID: 31182053]
[40]
Liang, S.; Gong, X.; Zhang, G.; Huang, G.; Lu, Y.; Li, Y. The lncRNA XIST interacts with miR-140/miR-124/iASPP axis to promote pancreatic carcinoma growth. Oncotarget, 2017, 8(69), 113701-113718.
[http://dx.doi.org/10.18632/oncotarget.22555] [PMID: 29371940]
[41]
Yang, M.; Wei, W. Long non-coding RNAs in retinoblastoma. Pathol. Res. Pract., 2019, 215(8) 152435
[http://dx.doi.org/10.1016/j.prp.2019.152435] [PMID: 31202519]
[42]
Zhang, J.; Li, W.Y.; Yang, Y.; Yan, L.Z.; Zhang, S.Y.; He, J.; Wang, J.X. LncRNA XIST facilitates cell growth, migration and invasion via modulating H3 histone methylation of DKK1 in neuroblastoma. Cell Cycle, 2019, 18(16), 1882-1892.
[http://dx.doi.org/10.1080/15384101.2019.1632134] [PMID: 31208278]
[43]
Xiao, H.; Liu, Y.; Liang, P.; Wang, B.; Tan, H.; Zhang, Y.; Gao, X.; Gao, J. TP53TG1 enhances cisplatin sensitivity of non-small cell lung cancer cells through regulating miR-18a/PTEN axis. Cell Biosci., 2018, 8, 23.
[http://dx.doi.org/10.1186/s13578-018-0221-7] [PMID: 29588850]
[44]
Chen, W.C.; Wang, W.C.; Okada, Y.; Chang, W.P.; Chou, Y.H.; Chang, H.H.; Huang, J.D.; Chen, D.Y.; Chang, W.C.; Chang, W.C. rs2841277 (PLD4) is associated with susceptibility and rs4672495 is associated with disease activity in rheumatoid arthritis. Oncotarget, 2017, 8(38), 64180-64190.
[http://dx.doi.org/10.18632/oncotarget.19419] [PMID: 28969061]
[45]
Bommhardt, U.; Schraven, B.; Simeoni, L. Beyond TCR Signaling: Emerging Functions of Lck in Cancer and Immunotherapy. Int. J. Mol. Sci., 2019, 20(14) E3500
[http://dx.doi.org/10.3390/ijms20143500] [PMID: 31315298]
[46]
Peronnet, E.; Nguyen, K.; Cerrato, E.; Guhadasan, R.; Venet, F.; Textoris, J.; Pachot, A.; Monneret, G.; Carrol, E.D. Evaluation of mRNA biomarkers to identify risk of hospital acquired infections in children admitted to paediatric intensive care unit. PLoS One, 2016, 11(3) e0152388
[http://dx.doi.org/10.1371/journal.pone.0152388] [PMID: 27015534]
[47]
Schürch, C.; Riether, C.; Matter, M.S.; Tzankov, A.; Ochsenbein, A.F. CD27 signaling on chronic myelogenous leukemia stem cells activates Wnt target genes and promotes disease progression. J. Clin. Invest., 2012, 122(2), 624-638.
[http://dx.doi.org/10.1172/JCI45977] [PMID: 22232214]
[48]
Lennon, M.J.; Jones, S.P.; Lovelace, M.D.; Guillemin, G.J.; Brew, B.J. Bcl11b-A critical neurodevelopmental transcription factor-roles in health and disease. Front. Cell. Neurosci., 2017, 11, 89.
[http://dx.doi.org/10.3389/fncel.2017.00089] [PMID: 28424591]
[49]
Sinha, S.; Borcherding, N.; Renavikar, P.S.; Crawford, M.P.; Tsalikian, E.; Tansey, M.; Shivapour, E.T.; Bittner, F.; Kamholz, J.; Olalde, H.; Gibson, E.; Karandikar, N.J. An autoimmune disease risk SNP, rs2281808, in SIRPG is associated with reduced expression of SIRPγ and heightened effector state in human CD8 T-cells. Sci. Rep., 2018, 8(1), 15440.
[http://dx.doi.org/10.1038/s41598-018-33901-1] [PMID: 30337675]
[50]
Sinha, S.; Renavikar, P.S.; Crawford, M.P.; Rodgers, J.W.; Tsalikian, E.; Tansey, M.; Karandikar, N.J. Autoimmunity-associated intronic SNP (rs2281808) detected by a simple phenotypic assay: Unique case or broader opportunity? Clin. Immunol., 2019, 198, 57-61.
[http://dx.doi.org/10.1016/j.clim.2018.12.018] [PMID: 30579937]
[51]
Murshid, A.; Gong, J.; Prince, T.; Borges, T.J.; Calderwood, S.K. Scavenger receptor SREC-I mediated entry of TLR4 into lipid microdomains and triggered inflammatory cytokine release in RAW 264.7 cells upon LPS activation. PLoS One, 2015, 10(4) e0122529
[http://dx.doi.org/10.1371/journal.pone.0122529] [PMID: 25836976]
[52]
Dubois, N.C.; Craft, A.M.; Sharma, P.; Elliott, D.A.; Stanley, E.G.; Elefanty, A.G.; Gramolini, A.; Keller, G. SIRPA is a specific cell-surface marker for isolating cardiomyocytes derived from human pluripotent stem cells. Nat. Biotechnol., 2011, 29(11), 1011-1018.
[http://dx.doi.org/10.1038/nbt.2005] [PMID: 22020386]
[53]
Li, W.; Wu, Y.F.; Xu, R.H.; Lu, H.; Hu, C.; Qian, H. miR-1246 releases RTKN2-dependent resistance to UVB-induced apoptosis in HaCaT cells. Mol. Cell. Biochem., 2014, 394(1-2), 299-306.
[http://dx.doi.org/10.1007/s11010-014-2108-1] [PMID: 24880483]
[54]
Yu, M.; Li, W.; Wang, Q.; Wang, Y.; Lu, F. Circadian regulator NR1D2 regulates glioblastoma cell proliferation and motility. Oncogene, 2018, 37(35), 4838-4853.
[http://dx.doi.org/10.1038/s41388-018-0319-8] [PMID: 29773903]


Rights & PermissionsPrintExport Cite as

Article Details

VOLUME: 23
ISSUE: 5
Year: 2020
Page: [369 - 380]
Pages: 12
DOI: 10.2174/1386207323666200401121204
Price: $65

Article Metrics

PDF: 30
HTML: 3
PRC: 1