The RBP2-BECN1-VEGFA axis orchestrates a self-amplifying circuit to drive malignant progression in gastric carcinoma.

OBJECTIVE: Gastric carcinoma (GC) is a leading cause of cancer-related mortality, often driven by epigenetic dysregulation. This study investigates the role of Retinoblastoma-binding protein 2 (RBP2), a chromatin-associated transcriptional regulator frequently overexpressed in GC. We specifically focus on elucidating how RBP2 functions as a transcriptional regulator​ within the autophagy-angiogenesis network and its impact on disease progression. METHODS: The regulatory axis was dissected using integrated approaches, including transcriptomic profiling, cellular and molecular biology assays, and in vivo animal models. Clinical specimen analysis was performed to correlate RBP2 expression with autophagy and angiogenesis markers. Functional validation involved gain- and loss-of-function experiments to delineate the signaling circuitry linking RBP2 to BECN1 and VEGFA. RESULTS: We discovered that RBP2 drives GC progression by establishing an autophagy-angiogenesis positive feedback loop. RBP2 transcriptionally regulates BECN1 through promoter-dependent mechanisms supported by dual-luciferase reporter and ChIP-qPCR assays, thereby inducing protective autophagy. This autophagy enhances VEGFA secretion, which upregulates RBP2 via the inactivation of the JNK/p53/miR-212 axis, thereby relieving post-transcriptional repression. This self-reinforcing circuit facilitates sustained gastric carcinogenesis. CONCLUSION: Our findings support a novel "RBP2-BECN1 -VEGFA-JNK/p53/miR-212-RBP2" regulatory axis that links epigenetic regulation to autophagic survival and angiogenic signaling. This study elucidates a key mechanism underlying GC pathogenesis and suggests potential targets for combinatorial therapeutic strategies.