Abstract

Helicobacter pylori is a gastric pathogen associated with the development of gastric cancer. By attaching to the gastric epithelium, it triggers signaling pathways that lead to effects ranging from apoptosis to cell proliferation. H. pylori has been shown to promote nuclear translocation of beta-catenin, inducing gene expression related to the cell cycle. However, recent studies indicate it also causes cell cycle arrest by stabilizing hypoxia-inducible factor 1-alpha (HIF-1 alpha). The mechanisms underlying these opposing effects remain unknown. Here, we explored the effects of H. pylori infection on beta-catenin and transcription factor 7-like 2 (TCF7L2, also known as TCF-4) interaction, as well as downstream transcriptional activity. We observed that, despite maintaining total and nuclear levels of beta-catenin and TCF-4, bacterial infection disassembled the beta-catenin/TCF-4 complex, as shown by co-localization and co-immunoprecipitation assays. These changes were followed by decreased TCF/lymphoid enhancer-binding factor (Lef)-dependent transcription and reduced cell proliferative capacity. Conversely, H. pylori promoted the association of beta-catenin and HIF-1 alpha in a protein complex that enhanced transcription of hypoxia response elements. Inhibition of HIF-1 alpha prevented this association and preserved beta-catenin/TCF-4 interaction, restoring TCF/Lef-dependent activity. The requirement of HIF-1 alpha was further confirmed by short hairpin RNA (shRNA) and by using a urease mutant strain unable to stabilize HIF-1 alpha. Interestingly, infection was associated with upregulation of HIF-1 alpha target genes involved in migration and invasion. Consequently, H. pylori increased cell invasion while decreasing cell proliferative capacity in a HIF-1 alpha-dependent manner. Thus, our results demonstrate that H. pylori decreases cell proliferation by reducing beta-catenin/TCF-4 interaction, while increasing beta-catenin/HIF-1 alpha complex formation, which is associated with cell invasion as an adaptive mechanism.