Enhanced COMP expression induced by Helicobacter pylori drives gastric cancer progression by NOTCH2/SMAD3 pathway

The main risk factor for gastric carcinogenesis is infection with Helicobacter pylori (H. pylori) that injects the bacterial oncoprotein cytotoxin-associated gene A (CagA). Aberrant cartilage oligomeric protein (COMP) expression is implicated in tumorigenesis and cancer development. However, the critical mediators participating in regulation of COMP and how COMP contributes to the progression of gastric cancer (GC) have not been elucidated.

To evaluate H. pylori-mediated transcriptional changes, RNA-seq was performed. The clinical relevance and prognostic potential of COMP in GC were examined via Western blot and IHC assays. Functional roles of COMP were further probed using in vitro cellular models and in vivo animal studies. Putative mechanistic networks were elucidated through chromatin immunoprecipitation (ChIP) and co-immunoprecipitation (Co-IP) experiments.

In GC cell lines and mouse models, both H. pylori colonization and its virulence factor CagA upregulated COMP at transcriptional and translational levels. COMP expression is markedly elevated in H. pylori-related GC and is associated with poor prognosis. The inhibition of COMP curtailed the pro-proliferative, metastatic, and epithelial-mesenchymal transition (EMT) capacities of the CagA in GC cells. H. pylori infection enhances COMP expression via the activation of KLF5. COMP binding to NOTCH2 and JAG1 facilitates the interaction between NOTCH2 and JAG1, hence activating downstream SMAD3, which promotes EMT in GC.

H. pylori infection depends on CagA/KLF5 to induce COMP expression and highlights the COMP/NOTCH2/SMAD3/EMT axis in modulating GC progression, which may reveal actionable targets for GC therapy.