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

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 (Krt19^CreErt/Aurka^flox/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 Krt19^CreErt/Aurka^flox/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.