The quantitative proteomics analysis of multi-stage gastric mucosal lesions associated with Helicobacter pylori...

Helicobacter pylori (H. pylori) infection is the principal etiological factor for gastric cancer (GC), which ranks as the fourth leading cause of cancer-related mortality globally. Although the Correa cascade describes the stepwise progression from chronic gastritis to intestinal-type GC, the molecular events underlying this "inflammation-to-cancer" transition remain incompletely characterized.

This study aimed to delineate stage-specific proteomic alterations across H. pylori-associated gastric mucosal lesions and to identify candidate progression-associated biomarkers in GC.

Label-free quantitative proteomic analysis (LC-MS/MS) was performed on gastric tissue specimens from 22 patients stratified into four histopathological stages: H. pylori-negative chronic non-atrophic gastritis (HpN-CG), H. pylori-positive chronic non-atrophic gastritis (HpC-CG), H. pylori-positive chronic atrophic gastritis (HpC-CAG), and intestinal-type GC. Functional enrichment (GO, KEGG), temporal clustering (Mfuzz), and protein-protein interaction (PPI) network analyses were conducted. Key hub genes were externally assessed using GEPIA RNA-seq data from TCGA and GTEx.

A total of 6,019 proteins were quantified. Differential expression analysis identified 771 DEPs between HpC-CG and HpN-CG, 101 DEPs between HpC-CAG and HpC-CG, and 535 DEPs between GC and HpC-CAG. Immune response pathways were up-regulated upon H. pylori infection, whereas oxidative phosphorylation was progressively suppressed throughout disease progression. Mfuzz clustering revealed that Cluster 4 ribosome-biogenesis proteins, including NIP7 and PDCD11 identified in the proteomic/PPI analysis, exhibited continuous up-regulation from precancerous stages to GC. External RNA-expression validation supported significant up-regulation of seven Cluster 4 hub genes, whereas Cluster 6 proteins did not show concordant transcript-level down-regulation.

This study provides a comprehensive proteomic landscape of H. pylori-driven gastric carcinogenesis. Cluster 4 ribosome-biogenesis proteins represent candidate progression-associated protein markers requiring further protein-level validation, while the progressive decline in oxidative phosphorylation underscores mitochondrial dysfunction as a hallmark of disease progression.