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Background <p>Metabolic reprogramming is a hallmark of gastric cancer (GC) and is primarily regulated by hypoxia-inducible factor 1-alpha (HIF-1α). <i>Helicobacter pylori</i> (<i>H. pylori</i>) infection promotes tumor progression via HIF-1α-dependent pathways, but the specific role and mechanism of its CagA protein in this process remain unclear.</p> Objective <p>This study aimed to elucidate the underlying mechanisms by which CagA promotes chemoresistance and aggressive phenotypes, with the focus on HIF-1α-mediated signal pathways.</p> Results <p>CagA-positive <i>H. pylori</i> infection enhanced oxaliplatin resistance, colony formation, and sphere-forming ability in GC cells without significantly affecting migration or invasion. Similarly, xenograft tumors derived from CagA-positive cells were larger and less responsive to oxaliplatin. Metabolically, CagA-positive infection reduces the oxygen consumption rate, increases the extracellular acidification rate and lactate production, and elevates glycolytic enzymes. HIF-1α expression was upregulated in CagA-positive clinical samples, cells, and tumor tissues, while silencing it could reverse the glycolytic shift induced by CagA and mitigated associated malignant features.</p> Conclusion <p>CagA promotes drug resistance and tumor malignancy in GC through HIF-1α-driven glycolytic reprogramming, underscoring the HIF-1α pathway as a promising target for therapeutic intervention in CagA-related malignancy.</p>

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Helicobacter pylori CagA protein confers aggressive phenotypes to gastric cancer cells through the HIF-1α-mediated metabolic reprogramming

  • 期刊论文

  • 发表日期：

    2025年9月25日

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  • Suhua Li,
  • Xuehong Wang

摘要

Background

Metabolic reprogramming is a hallmark of gastric cancer (GC) and is primarily regulated by hypoxia-inducible factor 1-alpha (HIF-1α). Helicobacter pylori (H. pylori) infection promotes tumor progression via HIF-1α-dependent pathways, but the specific role and mechanism of its CagA protein in this process remain unclear.

Objective

This study aimed to elucidate the underlying mechanisms by which CagA promotes chemoresistance and aggressive phenotypes, with the focus on HIF-1α-mediated signal pathways.

Results

CagA-positive H. pylori infection enhanced oxaliplatin resistance, colony formation, and sphere-forming ability in GC cells without significantly affecting migration or invasion. Similarly, xenograft tumors derived from CagA-positive cells were larger and less responsive to oxaliplatin. Metabolically, CagA-positive infection reduces the oxygen consumption rate, increases the extracellular acidification rate and lactate production, and elevates glycolytic enzymes. HIF-1α expression was upregulated in CagA-positive clinical samples, cells, and tumor tissues, while silencing it could reverse the glycolytic shift induced by CagA and mitigated associated malignant features.

Conclusion

CagA promotes drug resistance and tumor malignancy in GC through HIF-1α-driven glycolytic reprogramming, underscoring the HIF-1α pathway as a promising target for therapeutic intervention in CagA-related malignancy.