Identification of Unique Transcriptomic Signatures and Hub Genes Through RNA Sequencing and Integrated WGCNA and PPI Network Analysis in Nonerosive Reflux Disease

References

• Gyawali CP, Kahrilas PJ, Savarino E, et al. Modern diagnosis of GERD: the Lyon consensus. Gut. 2018;67(7):1351–1362. doi:10.1136/gutjnl-2017-314722
   PubMed Web of Science ®Google Scholar
• Yadlapati R, DeLay K. Proton pump inhibitor-refractory gastroesophageal reflux disease. Med Clin North Am. 2019;103(1):15–27. doi:10.1016/j.mcna.2018.08.002
   PubMed Web of Science ®Google Scholar
• Ustaoglu A, Nguyen A, Spechler S, et al. Mucosal pathogenesis in gastro-esophageal reflux disease. Neurogastroenterol Motil. 2020;32(12):e14022. doi:10.1111/nmo.14022
   PubMed Web of Science ®Google Scholar
• de Bortoli N, Ottonello A, Zerbib F, et al. Between GERD and NERD: the relevance of weakly acidic reflux. Ann N Y Acad Sci. 2016;1380(1):218–229. doi:10.1111/nyas.13169
   PubMed Web of Science ®Google Scholar
• Fock KM, Talley N, Goh KL, et al. Asia-Pacific consensus on the management of gastro-oesophageal reflux disease: an update focusing on refractory reflux disease and Barrett’s oesophagus. Gut. 2016;65(9):1402–1415.
   PubMed Web of Science ®Google Scholar
• Woodland P, Al-Zinaty M, Yazaki E, Sifrim D. In vivo evaluation of acid-induced changes in oesophageal mucosa integrity and sensitivity in non-erosive reflux disease. Gut. 2013;62(9):1256–1261. doi:10.1136/gutjnl-2012-302645
   PubMed Web of Science ®Google Scholar
• Woodland P, Sifrim D. Oesophageal mucosal barrier: a key factor in the pathophysiology of non-erosive reflux disease (NERD) and a potential target for treatment. Gut. 2014;63(5):705–706. doi:10.1136/gutjnl-2013-305101
   PubMed Web of Science ®Google Scholar
• Jovov B, Reed CC, Shaheen NJ, et al. Fragments of e-cadherin as biomarkers of non-erosive reflux disease. Dig Dis Sci. 2018;63(3):628–635. doi:10.1007/s10620-017-4815-4
   PubMed Web of Science ®Google Scholar
• Jovov B, Que J, Tobey NA, et al. Role of E-cadherin in the pathogenesis of gastroesophageal reflux disease. Am J Gastroenterol. 2011;106(6):1039–1047. doi:10.1038/ajg.2011.102
   PubMed Web of Science ®Google Scholar
• Chen H, Hu YH, Fang Y, et al. Nrf2 deficiency impairs the barrier function of mouse oesophageal epithelium. Gut. 2014;63(5):711–719. doi:10.1136/gutjnl-2012-303731
   PubMed Web of Science ®Google Scholar
• Suzuki N, Mihara H, Nishizono H, Tominaga M, Sugiyama T. Protease-activated receptor-2 up-regulates transient receptor potential vanilloid 4 function in mouse esophageal keratinocyte. Dig Dis Sci. 2015;60(12):3570–3578. doi:10.1007/s10620-015-3822-6
   PubMed Web of Science ®Google Scholar
• Guarino MP, Cheng L, Ma J, et al. Increased TRPV1 gene expression in esophageal mucosa of patients with non-erosive and erosive reflux disease. Neurogastroenterol Motil. 2010;22(7):746–751. doi:10.1111/j.1365-2982.2010.01514.x
   PubMed Web of Science ®Google Scholar
• Kandulski A, Wex T, Monkemuller K, et al. Proteinase-activated receptor-2 in the pathogenesis of gastroesophageal reflux disease. Am J Gastroenterol. 2010;105(9):1934–1943. doi:10.1038/ajg.2010.265
   PubMed Web of Science ®Google Scholar
• Wu L, Oshima T, Shan J, et al. PAR-2 activation enhances weak acid-induced ATP release through TRPV1 and ASIC sensitization in human esophageal epithelial cells. Am J Physiol Gastrointest Liver Physiol. 2015;309(8):G695–702. doi:10.1152/ajpgi.00162.2015
   PubMed Web of Science ®Google Scholar
• Souza RF, Huo XF, Mittal V, et al. Gastroesophageal reflux might cause esophagitis through a cytokine-mediated mechanism rather than caustic acid injury. Gastroenterology. 2009;137(5):1776–1784. doi:10.1053/j.gastro.2009.07.055
   PubMed Web of Science ®Google Scholar
• Dunbar KB, Agoston AT, Odze RD, et al. Association of acute gastroesophageal reflux disease with esophageal histologic changes. JAMA. 2016;315(19):2104–2112. doi:10.1001/jama.2016.5657
   PubMed Web of Science ®Google Scholar
• Isomoto H, Saenko VA, Kanazawa Y, et al. Enhanced expression of interleukin-8 and activation of nuclear factor kappa-B in endoscopy-negative gastroesophageal reflux disease. Am J Gastroenterol. 2004;99(4):589–597. doi:10.1111/j.1572-0241.2004.04110.x
   PubMed Web of Science ®Google Scholar
• Mönkemüller K, Wex T, Kuester D, et al. Interleukin-1beta and interleukin-8 expression correlate with the histomorphological changes in esophageal mucosa of patients with erosive and non-erosive reflux disease. Digestion. 2009;79(3):186–195. doi:10.1159/000211714
   PubMed Web of Science ®Google Scholar
• Taddei A, Fabbroni V, Pini A, et al. Cyclooxygenase-2 and inflammation mediators have a crucial role in reflux-related esophageal histological changes and Barrett’s esophagus. Dig Dis Sci. 2014;59(5):949–957. doi:10.1007/s10620-013-2975-4
   PubMed Web of Science ®Google Scholar
• Shan J, Oshima T, Muto T, et al. Epithelial-derived nuclear IL-33 aggravates inflammation in the pathogenesis of reflux esophagitis. J Gastroenterol. 2015;50(4):414–423. doi:10.1007/s00535-014-0988-1
   PubMed Web of Science ®Google Scholar
• Isomoto H, Wang A, Mizuta Y, et al. Elevated levels of chemokines in esophageal mucosa of patients with reflux esophagitis. Am J Gastroenterol. 2003;98(3):551–556. doi:10.1111/j.1572-0241.2003.07303.x
   PubMed Web of Science ®Google Scholar
• Isomoto H, Nishi Y, Kanazawa Y, et al. Immune and inflammatory responses in GERD and lansoprazole. J Clin Biochem Nutr. 2007;41(2):84–91. doi:10.3164/jcbn.2007012
   PubMed Web of Science ®Google Scholar
• O’Riordan JM, Abdel-Latif MM, Ravi N, et al. Proinflammatory cytokine and nuclear factor kappa-B expression along the inflammation-metaplasia-dysplasia-adenocarcinoma sequence in the esophagus. Am J Gastroenterol. 2005;100(6):1257–1264. doi:10.1111/j.1572-0241.2005.41338.x
   PubMed Web of Science ®Google Scholar
• Lyros O, Rafiee P, Nie L, et al. Dickkopf-1, the Wnt antagonist, is induced by acidic pH and mediates epithelial cellular senescence in human reflux esophagitis. Am J Physiol-Gastrointest Liver Physiol. 2014;306(7):G557–574. doi:10.1152/ajpgi.00153.2013
   PubMed Web of Science ®Google Scholar
• Zhang HY, Zhang X, Chen X, et al. Differences in activity and phosphorylation of MAPK enzymes in esophageal squamous cells of GERD patients with and without Barrett’s esophagus. Am J Physiol Gastrointest Liver Physiol. 2008;295(3):G470–G478. doi:10.1152/ajpgi.90262.2008
   PubMed Web of Science ®Google Scholar
• Shannon 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. doi:10.1101/gr.1239303
   PubMed Web of Science ®Google Scholar
• Zhou 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. doi:10.1038/s41467-019-09234-6
   PubMed Web of Science ®Google Scholar
• Langfelder P, Horvath S. WGCNA: an R package for weighted correlation network analysis. BMC Bioinform. 2008;9:559. doi:10.1186/1471-2105-9-559
   PubMed Web of Science ®Google Scholar
• Szklarczyk D, Morris JH, Cook H, et al. The STRING database in 2017: quality-controlled protein-protein association networks, made broadly accessible. Nucleic Acids Res. 2017;45(D1):D362–D368. doi:10.1093/nar/gkw937
   PubMed Web of Science ®Google Scholar
• 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 U S A. 2005;102(43):15545–15550. doi:10.1073/pnas.0506580102
   PubMed Web of Science ®Google Scholar
• 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. doi:10.1093/nar/gkt1248
   PubMed Web of Science ®Google Scholar
• Tong Z, Cui Q, Wang J, Zhou Y. TransmiR v2.0: an updated transcription factor-microRNA regulation database. Nucleic Acids Res. 2019;47(D1):D253–D258. doi:10.1093/nar/gky1023
   PubMed Web of Science ®Google Scholar
• Oki S, Ohta T, Shioi G, et al. ChIP-Atlas: a data-mining suite powered by full integration of public ChIP-seq data. EMBO Rep. 2018;19(12):e46255.
   PubMed Web of Science ®Google Scholar
• Hungin AP, Molloy-Bland M, Scarpignato C. Revisiting Montreal: new insights into symptoms and their causes, and implications for the future of GERD. Am J Gastroenterol. 2019;114(3):414–421. doi:10.1038/s41395-018-0287-1
   PubMed Web of Science ®Google Scholar
• Laczko R, Csiszar K. Lysyl Oxidase (LOX): functional contributions to signaling pathways. Biomolecules. 2020;10(8):1093. doi:10.3390/biom10081093
   PubMed Web of Science ®Google Scholar
• Rieder F, Fiocchi C, Rogler G. Mechanisms, management, and treatment of fibrosis in patients with inflammatory bowel diseases. Gastroenterology. 2017;152(2):340–350. doi:10.1053/j.gastro.2016.09.047
   PubMed Web of Science ®Google Scholar
• Cheng E, Souza RF, Spechler SJ. Eosinophilic esophagitis: interactions with gastroesophageal reflux disease. Gastroenterol Clin North Am. 2014;43(2):243–256. doi:10.1016/j.gtc.2014.02.004
   PubMed Web of Science ®Google Scholar
• Roudebush C, Catala-Valentin A, Andl T, Le Bras GF, Andl CD. Activin A-mediated epithelial de-differentiation contributes to injury repair in an in vitro gastrointestinal reflux model. Cytokine. 2019;123:154782. doi:10.1016/j.cyto.2019.154782
   PubMed Web of Science ®Google Scholar
• Beswick EJ, Grim C, Singh A, et al. Expression of programmed death-ligand 1 by human colonic CD90(+) stromal cells differs between ulcerative colitis and crohn’s disease and determines their capacity to suppress th1 cells. Front Immunol. 2018;9:1125. doi:10.3389/fimmu.2018.01125
   PubMed Web of Science ®Google Scholar
• Rodriguez P, Silva SD, Oxburgh L, et al. BMP signaling in the development of the mouse esophagus and forestomach. Development. 2010;137(24):4171–4176. doi:10.1242/dev.056077
   PubMed Web of Science ®Google Scholar
• Milano F, van Baal JW, Buttar NS, et al. Bone morphogenetic protein 4 expressed in esophagitis induces a columnar phenotype in esophageal squamous cells. Gastroenterology. 2007;132(7):2412–2421. doi:10.1053/j.gastro.2007.03.026
   PubMed Web of Science ®Google Scholar
• Kinchen J, Chen HH, Parikh K, et al. Structural remodeling of the human colonic mesenchyme in inflammatory bowel disease. Cell. 2018;175(2):372–386. doi:10.1016/j.cell.2018.08.067
   PubMed Web of Science ®Google Scholar
• Goffin L, Fagagnini S, Vicari A, et al. Anti-MMP-9 antibody: a promising therapeutic strategy for treatment of inflammatory bowel disease complications with fibrosis. Inflamm Bowel Dis. 2016;22(9):2041–2057. doi:10.1097/MIB.0000000000000863
   PubMed Web of Science ®Google Scholar
• Zavala-Solares MR, Fonseca-Camarillo G, Valdovinos M, et al. Gene expression profiling of inflammatory cytokines in esophageal biopsies of different phenotypes of gastroesophageal reflux disease: a cross-sectional study. BMC Gastroenterol. 2021;21(1):201. doi:10.1186/s12876-021-01707-7
   PubMed Web of Science ®Google Scholar
• Sandner A, Illert J, Koitzsch S, Unverzagt S, Schön I. Reflux induces DNA strand breaks and expression changes of MMP1+9+14 in a human miniorgan culture model. Exp Cell Res. 2013;319(19):2905–2915. doi:10.1016/j.yexcr.2013.09.004
   PubMed Web of Science ®Google Scholar
• Bergers G, Brekken R, McMahon G, et al. Matrix metalloproteinase-9 triggers the angiogenic switch during carcinogenesis. Nat Cell Biol. 2000;2(10):737–744. doi:10.1038/35036374
   PubMed Web of Science ®Google Scholar
• Jones MK, Kawanaka H, Baatar D, et al. Gene therapy for gastric ulcers with single local injection of naked DNA encoding VEGF and angiopoietin-1. Gastroenterology. 2001;121(5):1040–1047. doi:10.1053/gast.2001.29308
   PubMed Web of Science ®Google Scholar
• Auvinen MI, Sihvo EIT, Ruohtula T, et al. Incipient angiogenesis in Barrett’s epithelium and lymphangiogenesis in Barrett’s adenocarcinoma. J Clin Oncol. 2002;20(13):2971–2979. doi:10.1200/JCO.2002.09.011
   PubMed Web of Science ®Google Scholar
• Zhang Q, Agoston AT, Pham TH, et al. Acidic bile salts induce epithelial to mesenchymal transition via VEGF signaling in non-neoplastic barrett’s cells. Gastroenterology. 2019;156(1):130–144. doi:10.1053/j.gastro.2018.09.046
   PubMed Web of Science ®Google Scholar
• Zhang Q, Yu C, Peng S, et al. Autocrine VEGF signaling promotes proliferation of neoplastic barrett’s epithelial cells through a PLC-dependent pathway. Gastroenterology. 2014;146(2):461–472.e466. doi:10.1053/j.gastro.2013.10.011
   PubMed Web of Science ®Google Scholar