Tapia Héctor A, García-Navarrete Camila, Silva Patricio, Lizana Joaquín, Fonfach Carla, Pezoa-Soto Ignacio, Flores Tania, Hernández Nadia, Peña-Oyarzún Daniel, Toledo Jorge, Hernández-Gutiérrez Safka, Herrera Daniela, Varas-Godoy Manuel, Bravo Denisse, Torres Vicente A
Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago, Chile.
Millennium Institute on Immunology and Immunotherapy (MIII), Universidad de Chile, Santiago, Chile.
FEBS J. 2025 Jul 7. doi: 10.1111/febs.70179.
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 β-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-1α). The mechanisms underlying these opposing effects remain unknown. Here, we explored the effects of H. pylori infection on β-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 β-catenin and TCF-4, bacterial infection disassembled the β-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 β-catenin and HIF-1α in a protein complex that enhanced transcription of hypoxia response elements. Inhibition of HIF-1α prevented this association and preserved β-catenin/TCF-4 interaction, restoring TCF/Lef-dependent activity. The requirement of HIF-1α was further confirmed by short hairpin RNA (shRNA) and by using a urease mutant strain unable to stabilize HIF-1α. Interestingly, infection was associated with upregulation of HIF-1α target genes involved in migration and invasion. Consequently, H. pylori increased cell invasion while decreasing cell proliferative capacity in a HIF-1α-dependent manner. Thus, our results demonstrate that H. pylori decreases cell proliferation by reducing β-catenin/TCF-4 interaction, while increasing β-catenin/HIF-1α complex formation, which is associated with cell invasion as an adaptive mechanism.
幽门螺杆菌是一种与胃癌发生相关的胃部病原体。通过附着于胃上皮细胞，它触发信号通路，导致从细胞凋亡到细胞增殖等一系列效应。幽门螺杆菌已被证明可促进β-连环蛋白的核转位，诱导与细胞周期相关的基因表达。然而，最近的研究表明，它还通过稳定缺氧诱导因子1α（HIF-1α）导致细胞周期停滞。这些相反效应背后的机制仍然未知。在这里，我们探讨了幽门螺杆菌感染对β-连环蛋白与转录因子7样2（TCF7L2，也称为TCF-4）相互作用以及下游转录活性的影响。我们观察到，尽管β-连环蛋白和TCF-4的总量和核水平保持不变，但细菌感染使β-连环蛋白/TCF-4复合物解体，共定位和免疫共沉淀分析表明了这一点。这些变化随后伴随着TCF/淋巴样增强子结合因子（Lef）依赖性转录的减少和细胞增殖能力的降低。相反，幽门螺杆菌促进β-连环蛋白与HIF-1α在一种蛋白质复合物中的结合，该复合物增强了缺氧反应元件的转录。抑制HIF-1α可阻止这种结合并保留β-连环蛋白/TCF-4相互作用，恢复TCF/Lef依赖性活性。短发夹RNA（shRNA）以及使用无法稳定HIF-1α的脲酶突变菌株进一步证实了对HIF-1α的需求。有趣的是，感染与参与迁移和侵袭的HIF-1α靶基因的上调有关。因此，幽门螺杆菌以HIF-1α依赖性方式增加细胞侵袭，同时降低细胞增殖能力。因此，我们的结果表明，幽门螺杆菌通过减少β-连环蛋白/TCF-4相互作用来降低细胞增殖，同时增加β-连环蛋白/HIF-1α复合物的形成，这与作为一种适应性机制的细胞侵袭有关。
