Abstract
H. pylori infection is one of the leading causes of gastric cancer and the pathogenicity of H. pylori infection is associated with its ability to induce chronic inflammation and apoptosis resistance. While H. pylori infection-induced expression of pro-inflammatory cytokines for chronic inflammation is well studied, the molecular mechanism underlying the apoptosis resistance in infected cells is not well understood. In this study, we demonstrated that H. pylori infection-induced apoptosis resistance in gastric epithelial cells triggered by Raptinal, a drug that directly activates caspase-3. This resistance resulted from the induction of cIAP2 (encoded by BIRC3) since depletion of BIRC3 by siRNA or inhibition of cIAP2 via BV6 reversed H. pylori-suppressed caspase-3 activation. The induction of cIAP2 was regulated by H. pylori-induced BIRC3 eRNA synthesis. Depletion of BIRC3 eRNA decreased H. pylori-induced cIAP2 and reversed H. pylori-suppressed caspase-3 activation. Mechanistically, H. pylori stimulated the recruitment of bromodomain-containing factor Brd4 to the enhancer of BIRC3 and promoted BIRC3 eRNA and mRNA synthesis. Inhibition of Brd4 diminished the expression of BIRC3 eRNA and the anti-apoptotic response to H. pylori infection. Importantly, H. pylori isogenic cagA-deficient mutant failed to activate the synthesis of BIRC3 eRNA and the associated apoptosis resistance. Finally, in primary human gastric epithelial cells, H. pylori also induced resistance to Raptinal-triggered caspase-3 activation by activating the Brd4-dependent BIRC3 eRNA synthesis in a CagA-dependent manner. These results identify a novel function of Brd4 in H. pylori-mediated apoptosis resistance via activating BIRC3 eRNA synthesis, suggesting that Brd4 could be a potential therapeutic target for H. pylori-induced gastric cancer.
Highlights
Prevention of apoptosis by bacterial pathogens has emerged as a new trait of bacterial pathogenesis[1]
H. pylori infection-associated chronic inflammation and apoptosis resistance contribute to the development of gastric diseases, including gastritis and gastric cancer[39]
Since H. pylori CagA uses diverse pathways to activate NF-κB, which regulates the expression of cIAP214,19,32, it is possible that CagA utilizes activation of NF-κB to regulate the expression of BIRC3 enhancer RNA (eRNA) and the production of cIAP2
Summary
Prevention of apoptosis by bacterial pathogens has emerged as a new trait of bacterial pathogenesis[1]. Accumulating evidence indicates that the ability to inhibit apoptosis during infection provides the bacterial pathogens with a survival advantage for the establishment of infection[1]. H. pylori is a Gram-negative bacterium that colonizes the gastric epithelium, causing chronic gastric. IV secretion system that injects the bacterial virulence factor CagA into host epithelial cells[3]. CagA has been demonstrated to be critical for H. pylori-associated gastric cancer since infection with CagA-positive H. pylori strains is associated with an increased risk for gastric cancer compared to infection with CagA-negative strains[4,5]. The role of CagA in the pro-inflammatory cytokine production has been heavily studied, its contribution to cell survival is much less clear.
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