Abstract / Summary
Gastric cancer (GC) is a major contributor to cancer-related mortality worldwide, and Helicobacter pylori (HP) infection is considered a well-established risk factor for GC development. However, the molecular mechanisms underlying HP-associated GC progression remain incompletely understood. In this study, we investigated the role of ONECUT2 and YOD1 in HP-associated GC. Clinical samples were collected, including para‑carcinoma tissues from both HP‑negative and HP‑positive gastric cancer patients, as well as tumor tissues stratified into HP‑negative and HP‑positive groups. In vitro model of AGS/HGC-27 cells infected and non-infected with HP were established, and the expression levels of ONECUT2, YOD1, STAT3, and PD-L1 by qPCR and Western blot was detected. Cell proliferation, migration, and invasion abilities were evaluated using CCK-8, EdU, clone formation, and Transwell assays. The transcriptional regulatory effect of ONECUT2 on YOD1 through dual luciferase reporter gene assay and chromatin immunoprecipitation (ChIP) assay were verified. ShRNA and overexpression vectors elucidated the mechanism of the ONECUT2/YOD1/STAT3/PD-L1 signaling axis. ONECUT2, YOD1, and PD-L1 were significantly upregulated in HP-infected gastric tissues and cells. The knockdown of ONECUT2 attenuated proliferation, migration of AGS/HGC-27 cells under HP infection. Mechanistically, ONECUT2 transcriptionally activated YOD1 expression, which subsequently stabilized STAT3 and promoted PD-L1 upregulation. Furthermore, YOD1 overexpression partially rescued the inhibitory effects of ONECUT2 depletion on malignant phenotypes through the STAT3/PD-L1 signaling pathway. Collectively, these findings demonstrated that ONECUT2 promotes malignant progression in HP-associated GC through transcriptional activation of YOD1 and subsequent regulation of the STAT3/PD-L1 signaling cascade. The upregulation of PD-L1 through this axis suggests a potential role in immune-related regulation in GC. ONECUT2, YOD1, and PD-L1 were significantly upregulated in HP-infected gastric tissues and cells. YOD1 overexpression rescued the malignant progression inhibited by ONECUT2 knockdown via the STAT3/PD-L1 axis.