Actin gamma smooth muscle 2 drives proliferation, metastasis, and 5-Fluorouracil resistance in gastric cancer: insights from a Recurrence-Related Gene Signature

BACKGROUND: Gastric cancer is characterized by high recurrence rates after curative treatment, significantly contributing to poor survival outcomes. Current clinicopathological parameters inadequately predict recurrence risk, highlighting the need for robust molecular signatures to guide personalized therapy. METHODS: We analyzed gene expression profiles from multiple datasets to identify recurrence-associated genes in gastric cancer. A novel Recurrence-Related Gene Signature (RRGS) was constructed using LASSO regression, and its prognostic value was validated across independent cohorts. Functional validation of actin gamma smooth muscle 2 (ACTG2), which is encoded by the ACTG2 gene, was performed through in vitro knockdown experiments, zebrafish xenograft models, and chemoresistance analyses to assess its role as a key gene product in RRGS. RESULTS: We identified 72 consistently upregulated and 1 downregulated DEG across the two datasets, which were enriched in focal adhesion, ECM-receptor interaction, and PI3K-Akt signaling. A 32-gene RRGS reliably predicted recurrence risk and correlated with immune cell infiltration patterns. Among these genes, ACTG2 emerged as a key driver of gastric cancer aggressiveness, as its silencing significantly diminished tumor cell proliferation, migration, and invasion, and increased 5-fluorouracil sensitivity both in vitro and in vivo. Elevated ACTG2 protein expression was further validated immunohistochemically in recurrent patient tumors. CONCLUSION: Our findings highlight RRGS may serve as a prognostic tool and indicate that ACTG2 may plays an important role in both gastric cancer progression and chemotherapy resistance. Targeting ACTG2 or its downstream pathways may offer novel therapeutic opportunities to enhance treatment efficacy for patients with gastric cancer.