Abstract
Objective Periodontitis is a highly prevalent oral infectious disease and has been increasingly associated with H. pylori infection, gastric inflammation, and gastric cancer but little is known about epigenetic machinery underlying this potentially bidirectional association. The present study is aimed at identifying key deregulated miRNA, their associated genes, signaling pathways, and compounds linking periodontitis with H. pylori-associated peptic ulcer disease. Methods miRNA expression datasets for periodontitis-affected and H. pylori-associated peptic ulcer disease-affected tissues were sought from the GEO database. Differentially expressed miRNA (DEmiRNAs) were identified and the overlapping, shared-DEmiRNA between both datasets were determined. Shared-DEmiRNA-target networks construction and functional analyses were constructed using miRNet 2.0, including shared-DEmiRNA-gene, shared-DEmiRNA-transcription factor (TF), and shared-DEmiRNA-compound networks. Functional enrichment analysis for shared DEmiRNA-gene and shared DEmiRNA-TF networks was performed using the KEGG, Reactome, and Geno Ontology (GO) pathways. Results 11 shared-DEmiRNAs were identified, among which 9 showed similar expression patterns in both diseases, and 7 were overexpressed. miRNA hsa-hsa-mir-155-5p and hsa-mir-29a-3p were top miRNA nodes in both gene and TF networks. The topmost candidate miRNA-deregulated genes were PTEN, CCND1, MDM2, TNRC6A, and SCD while topmost deregulated TFs included STAT3, HIF1A, EZH2, CEBPA, and RUNX1. Curcumin, 5-fluorouracil, and the gallotanin 1,2,6-Tri-O-galloyl-beta-D-glucopyranose emerged as the most relevant linkage compound targets. Functional analyses revealed multiple cancer-associated pathways, PI3K pathways, kinase binding, and transcription factor binding among as enriched by the network-associated genes and TFs. Conclusion Integrative analysis of deregulated miRNAs revealed candidate molecular mechanisms comprising of top miRNA, their gene, and TF targets linking H. pylori-infected peptic ulcer disease with periodontitis and highlighted compounds targeting both diseases. These findings provide basis for directing future experimental research.
Highlights
Periodontitis is a multifactorial infectious disease characterized by the inflammatory destruction of the supporting structures of the teeth in response to a dysbiotic dental plaque biofilm [1]
1200 miRNA were retained in the analysis for the GSE54710 dataset, and a total of 172 significant periodontitis-associated DEmiRNA were identified, whereas 425 miRNAs were retained for the GSE32174 dataset analysis and 82 significant H. pylori infection-associated DEmiRNA were identified (Supplementary Table-S1). 177 DEmiRNA were overexpressed, and 55 DEmiRNA were underexpressed as compared to controls in periodontitis-affected tissue
Similar expression patterns were evident in case of 9 shared-DE miRNAs, where overexpression was noted in 7 and underexpression was seen in 2 shared-DEmiRNAs as compared to control tissues in both conditions. 2 shared-DEmiRNAs, hsa-miR-652 and hasmiR-30a, showed opposing expression patterns in both the conditions, with underexpression as compared to control in case of H. pylori infection but overexpression in case of periodontitis-affected tissue
Summary
Periodontitis is a multifactorial infectious disease characterized by the inflammatory destruction of the supporting structures of the teeth in response to a dysbiotic dental plaque biofilm [1]. Emerging evidence has highlighted an association of severe periodontal disease with peptic ulcer disease, chronic gastritis [3, 4], and with gastric carcinogenesis [5]. Considering the serious global burden imposed by gastric cancer [9], the association of H. pylori infection and gastric inflammation with periodontal disease. Several studies have identified the presence of a reservoir of H. pylori in the oral microflora of periodontitis patients [10,11,12,13]. The treatment of periodontitis has been found to improve gastric H. pylori elimination among peptic ulcer disease patients in multiple trials [14]. Others have suggested oral and gastric H. pylori infections may comprise a risk factor for periodontitis [13, 15]. Experimental data has shown that H. pylori infection and its virulence factor CagA can exert proinflammatory effects and promote the growth of periodontal pathogens [18]
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