Helicobacter pylori Exploit Short-Chain Fatty Acids-Induced CAPZA1 Overexpression to Emerge CD44v9-Positive Stemness

Area of Science:

• Gastroenterology and Oncology
• Microbiology and Immunology
• Molecular Biology

Background:

• Helicobacter pylori infection is a major risk factor for gastric cancer, yet the precise molecular mechanisms driving carcinogenesis remain unclear.
• A small subset of H. pylori-infected individuals develop gastric cancer, indicating critical host- or pathogen-driven factors influencing disease progression.
• This study investigates the role of CD44v9-positive cell generation in H. pylori-infected gastric mucosa as a key event in gastric carcinogenesis.

Purpose of the Study:

• To elucidate the molecular mechanisms underlying selective gastric carcinogenesis in H. pylori-infected individuals.
• To investigate the role of short-chain fatty acids (SCFAs) in the induction of CD44v9-positive cells.
• To evaluate the association between SCFA concentrations, microbiota composition, and gastric cancer risk in H. pylori-infected patients.

Main Methods:

• Utilized H. pylori infection models in human gastric adenocarcinoma cells, mice, and gastric organoids.
• Examined SCFA effects on CD44v9-positive cell induction using western blotting and immunofluorescence.
• Analyzed SCFA concentrations and microbiota composition in gastric juice from H. pylori-infected patients.

Main Results:

• Propionate and butyrate induced capping actin protein of muscle Z-line α subunit 1 (CAPZA1) overexpression via histone deacetylase inhibition.
• SCFA-induced CAPZA1 overexpression led to H. pylori oncoprotein CagA accumulation and enhanced CD44v9 expression.
• Elevated intragastric propionate and butyrate levels and enriched SCFA-producing bacteria were observed in patients with early gastric cancer.

Conclusions:

• SCFA-induced CAPZA1-overexpressing cells create a niche supporting CagA activity and promoting CD44v9-positive cancer stem-like cells.
• This study reveals novel early molecular events in H. pylori-associated gastric carcinogenesis.
• Findings may inform future strategies for the early detection and intervention of gastric cancer.