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<p>Aurora kinase A (AURKA) is frequently overexpressed in gastrointestinal cancers. <i>Helicobacter pylori (H. pylori</i>) infection is a significant risk factor for gastric carcinogenesis. LGR5, a stem cell marker in the stomach, plays an important role in gastric tumorigenesis. This study investigates the link between AURKA and LGR5 in response to <i>H. pylori</i> infection in gastric cancer. We analyzed publicly available datasets, gastric cancer cell lines, patient-derived organoids and xenografts (PDOs and PDXs), mouse models, and de-identified human tissue samples. We found a strong association between <i>AURKA</i> and <i>LGR5</i> expression levels in gastric cancer tissues. In vitro and in vivo analyses showed increased AURKA and LGR5 protein levels in response to <i>H. pylori</i> infection. Using cell models and PDOs, we demontrated an AURKA-dependent induction of LGR5, whereas genetic knockdown or pharmacologic inhibition of AURKA abolished the <i>H. pylori</i>-induced increase in LGR5 by enhancing LGR5 ubiquitination. Mechanistically, AURKA interacted with STAMBP, suppressing LGR5 deubiquitination and thereby&#xa0;promoting its stabilization. Using a tamoxifen-induced conditional knockout (CKO) mouse model of <i>Aurka</i> (<i>Krt19</i><sup><i>CreErt</i></sup>/<i>Aurka</i><sup>flox/flox</sup>), we detected a lower&#xa0;baseline expression of LGR5 in gastric glands, with reduced induction following <i>H. pylori</i> infection, compared to controls. The <i>Aurka</i> CKO mouse model was crossed with the <i>Tff1</i><sup><i>-/-</i></sup> model of gastric tumorigenesis to create the <i>Krt19</i><sup><i>CreErt</i></sup>/<i>Aurka</i><sup>flox/flox</sup> /<i>Tff1</i><sup>-/-</sup> mouse model. AURKA knockout, after tamoxifen treatment, significantly reduced the LGR5 protein level and led to a marked decrease in antral thickness. In PDX models, the use of a combination treatment of AMG900 (a pan-AURORA inhibitor) with docetaxel was more effective than monotherapy, lowering LGR5 levels and suppressing tumor growth. In summary, there is a functional link between AURKA and LGR5, mediated by STAMBP to promote stem-like properties and enhance cell survival in gastric tumorigenesis. Targeting the AURKA-LGR5 axis is a potential therapeutic strategy.</p>

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AURKA regulates LGR5 in response to Helicobacter Pylori infection by modulating its deubiquitination

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月11日

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  • Ahmed Gomaa,
  • Selma Maacha,
  • Mohammed Soutto,
  • Silvia Giordano,
  • Nadeem Bhat,
  • Shria Kumar,
  • Oliver G. McDonald,
  • Wael El-Rifai

摘要

Aurora kinase A (AURKA) is frequently overexpressed in gastrointestinal cancers. Helicobacter pylori (H. pylori) infection is a significant risk factor for gastric carcinogenesis. LGR5, a stem cell marker in the stomach, plays an important role in gastric tumorigenesis. This study investigates the link between AURKA and LGR5 in response to H. pylori infection in gastric cancer. We analyzed publicly available datasets, gastric cancer cell lines, patient-derived organoids and xenografts (PDOs and PDXs), mouse models, and de-identified human tissue samples. We found a strong association between AURKA and LGR5 expression levels in gastric cancer tissues. In vitro and in vivo analyses showed increased AURKA and LGR5 protein levels in response to H. pylori infection. Using cell models and PDOs, we demontrated an AURKA-dependent induction of LGR5, whereas genetic knockdown or pharmacologic inhibition of AURKA abolished the H. pylori-induced increase in LGR5 by enhancing LGR5 ubiquitination. Mechanistically, AURKA interacted with STAMBP, suppressing LGR5 deubiquitination and thereby promoting its stabilization. Using a tamoxifen-induced conditional knockout (CKO) mouse model of Aurka (Krt19CreErt/Aurkaflox/flox), we detected a lower baseline expression of LGR5 in gastric glands, with reduced induction following H. pylori infection, compared to controls. The Aurka CKO mouse model was crossed with the Tff1-/- model of gastric tumorigenesis to create the Krt19CreErt/Aurkaflox/flox /Tff1-/- mouse model. AURKA knockout, after tamoxifen treatment, significantly reduced the LGR5 protein level and led to a marked decrease in antral thickness. In PDX models, the use of a combination treatment of AMG900 (a pan-AURORA inhibitor) with docetaxel was more effective than monotherapy, lowering LGR5 levels and suppressing tumor growth. In summary, there is a functional link between AURKA and LGR5, mediated by STAMBP to promote stem-like properties and enhance cell survival in gastric tumorigenesis. Targeting the AURKA-LGR5 axis is a potential therapeutic strategy.