Role of FNDC1 and Gβ2 in suppression of the β-catenin destruction complex and promotion of gastric cancer malignancy.

e16478 Background: Gastric cancer (GC) is a leading cause of cancer-related deaths with high recurrence rates. Fibronectin domain-containing protein 1 (FNDC1) is implicated in GC progression, but its molecular mechanisms remain unclear. Methods: Multi-omics analyses (TCGA, GEO datasets) were used to assess FNDC1 expression and clinical correlation. In vitro (cell proliferation, invasion, EMT markers) and in vivo (xenograft) experiments, combined with molecular assays (Co-IP, WB, ChIP), explored FNDC1’s function and mechanism. Results: FNDC1 was significantly upregulated in GC, correlating with advanced clinicopathological features and poor prognosis. Knockdown of FNDC1 suppressed GC cell proliferation, invasion, and metastasis by inhibiting EMT and Wnt/β-catenin signaling. Mechanistically, FNDC1 competitively bound the WD5 domain (residues 224-254) of Gβ2, disrupting Gβγ-Dvl1 interaction. This prevented Dvl1 degradation, promoted Axin1 ubiquitination, and destabilized the β-catenin destruction complex (GSK3β-APC-Axin1), leading to β-catenin accumulation and Wnt pathway activation. Conclusions: FNDC1 drives GC malignancy by targeting the Gβ2-Dvl1 axis to activate Wnt/β-catenin signaling, suggesting FNDC1 as a novel prognostic biomarker and therapeutic target.