Differentially Expressed mRNAs and Their Long Noncoding RNA Regulatory Network with Helicobacter pylori-Associated Diseases including Atrophic Gastritis and Gastric Cancer

Abstract

Background: Helicobacter pylori (Hp) infection is the strongest risk factor for gastric cancer (GC). However, the mechanisms of Hp-associated GC remain to be explored.

Methods: The gene expression profiling (GSE111762) data were downloaded from the GEO database. Differentially expressed genes (DEGs) between normal samples (NO) and Hp-atrophic gastritis (GA) or Hp-GA and Hp-GC were identified by GEO2R. Gene Ontology and pathway enrichment analysis were performed using the DAVID database. lncRNA-TF-mRNA and ceRNA regulation networks were constructed using Cytoscape. The cross-networks were obtained by overlapping molecules of the above two networks. GSE27411 and GSE116312 datasets were employed for validation.

Results: DEGs between NO and Hp-GA are linked to the activity of inward rectifying potassium channels, digestion, etc. DEGs between Hp-GA and Hp-GC were associated with digestion, positive regulation of cell proliferation, etc. According to the lncRNA-TF-mRNA network, 63 lncRNAs, 12 TFs, and 209 mRNAs were involved in Hp-GA while 16 lncRNAs, 11 TFs, and 92 mRNAs were contained in the Hp-GC network. In terms of the ceRNA network, 120 mRNAs, 18 miRNAs, and 27 lncRNAs were shown in Hp-GA while 72 mRNAs, 8 miRNAs, and 1 lncRNA were included in the Hp-GC network. In the cross-network, we found that immune regulation and differentiation regulation were important in the process of NO-GA. Neuroendocrine regulation was mainly related to the process of GA-GC. In the end, we verified that CDX2 plays an important role in the pathological process of NO to Hp-GA. Comparing Hp-GA with Hp-GC, DEGs (FPR1, TFF2, GAST, SST, FUT9, and SHH), TF, and GATA5 were of great significance.

Conclusions: We identified the DEGs, and their lncRNA regulatory network of Hp-associated diseases might provide insights into the mechanism between Hp infection and GC. Furthermore, in-depth studies of the molecules might be useful to explore the multistep process of gastric diseases.

Figure 1

General workflow of the DEG screening and network construction.

Figure 2

Volcano plot of the DEGs in the gene expression dataset GSE111762. (a) Red color is indicative of upregulated genes and green color of downregulated genes in normal vs. Hp-GA. (b) Red color is indicative of upregulated genes and green color of downregulated genes in Hp-GA vs. Hp-GC. Gray color indicates genes that are not differentially expressed in a statistically significant manner (the cutoff values of FDR < 0.05 and ∣logFC | >2).

Figure 3

Bubble plot for GO enrichment of DEGs in (a) normal vs. Hp-GA and (b) Hp-GA vs. Hp-GC. The gene ratio is assigned to the x-axis and the description of pathway to the y-axis. The area of the displayed graphic is proportional to the number of genes assigned to the term, and the color corresponds to the adjusted P value.

Figure 4

lncRNA-TF-mRNA regulatory networks of (a) Hp-GA and (b) Hp-GC. Pink squares indicate lncRNAs, blue diamonds indicate TFs, orange circles indicate target genes, and size increases with the degree.

Figure 5

ceRNA regulatory networks of (a) Hp-GA and (b) Hp-GC. Pink squares indicate lncRNAs, green hexagons indicate miRNAs, orange circles indicate target genes, and size increases with the degree.

Figure 6

Cross-networks of (a) Hp-GA and (b) Hp-GC. Pink squares indicate lncRNAs, green hexagons indicate miRNAs, yellow diamonds indicate TFs, orange circles indicate target genes, and size increases with the degree.

Figure 7

(a) Validation of DEGs and TFs. Validation of DEGs and TFs related to Hp-GA in the GSE27411 dataset. (b–i) Validation of DEGs and TFs related to Hp-GC in the GSE116312 dataset.