SRY-box transcription factor 7 functions as a tumor suppressor regulating Wnt signaling and cancer stemness with its promoter methylation as a potential biomarker

BACKGROUND: Wnt signaling, critical for development, is often dysregulated in cancer via genetic or/and epigenetic changes. SOX7, a high mobility group protein, is downregulated in cancers, but its alterations and underlying mechanism in gastric cancer (GsCa) pathogenesis remain to be clearly defined. METHODS: SOX7 mRNA expression and promoter methylation were analyzed in GsCa. Functional impacts were assessed through assays for colony formation, proliferation (CCK-8), cell cycle/apoptosis (flow cytometry), migration/invasion (wound healing, Transwell), and ferroptosis. Mechanistic studies involving Western blot, immunofluorescence, dual-luciferase reporter assays, chromatin immunoprecipitation (ChIP)-qPCR, and bidirectional rescue experiments focused on the Wnt/β-catenin signaling and cancer stemness markers. RESULTS: SOX7 was widely expressed in normal tissues, including stomach, but was frequently downregulated in GsCa due to promoter CpG methylation, which correlated with worse overall patient survival. Functionally, SOX7 restoration inhibited GsCa cell growth by inducing G0/G1 arrest, ferroptosis, and apoptosis. It also suppressed migration and invasion by inhibiting epithelial-mesenchymal transition (EMT) and cancer stemness. Mechanistically, SOX7 is localized to nuclear speckles and antagonized Wnt/β-catenin signaling through sequestering active β-catenin in the cytoplasm, directly binding to Wnt target gene promoters (e.g., c-MYC), and competitively β-catenin displacement. Bidirectional rescue experiments confirmed its tumor-suppressive functions dependent on inactivation of β-catenin. CONCLUSIONS: SOX7 is a tumor suppressor in GsCa frequently inactivated by promoter methylation. It suppresses tumorigenesis by direct antagonizing Wnt signaling, thereby inhibiting EMT and stemness. SOX7 promoter methylation is a potential biomarker for GsCa prognosis and detection.