TRAF1 promotes the progression of Helicobacter pylori-associated gastric cancer through EGFR/STAT/OAS signalling

Abstract

Aims

Helicobacter pylori (H. pylori) is associated with various gastric diseases and is one of the pathogenic factors of gastric cancer (GC). We found that H. pylori induce the expression of TRAF1, but its mechanism of action is still unclear. Therefore, we wanted to determine whether TRAF1 is involved in the mechanism of H. pylori-related GC progression.

Materials and methods

In this study, we analysed TRAF1 expression and its prognostic significance using clinical specimens, performed functional studies involving TRAF1 overexpression or knockdown in cellular models, identified downstream signalling pathways regulated via RNA-seq, validated these mechanisms through pathway blockade and rescue experiments, and further confirmed the findings in an H. pylori-infected gastritis mouse model.

Key findings

TRAF1 expression was significantly elevated in GC tissues and served as a poor prognostic biomarker. TRAF1 promoted GC cell proliferation, migration and invasion. RNA-seq analysis revealed that TRAF1 activated the EGFR/STAT/OAS signalling axis, upregulated STAT3 expression and increased the transcription of the OAS gene family. Pharmacological inhibition with ruxolitinib and AG490 effectively blocked EGFR/STAT/OAS signalling. In H. pylori-treated cell models, H. pylori infection activated the EGFR/STAT/OAS signalling axis. In vivo, we established an H. pylori-induced gastritis mouse model to validate the activation of this signalling pathway during the gastritis–carcinoma transition.

Significance

TRAF1 may promote the proliferation, migration and invasion of H. pylori-associated GC by activating the EGFR/STAT/OAS signalling axis, suggesting that TRAF1 is a promising novel prognostic biomarker and therapeutic target for this malignancy.