MicroRNA‐431‐5p inhibits angiogenesis, lymphangiogenesis, and lymph node metastasis by affecting TGF‐β1/SMAD2/3 signaling via ZEB1 in gastric cancer

Abstract Accumulating evidence suggests that lymphangiogenesis plays a crucial role in lymphatic metastasis, leading to tumor immune tolerance. However, the specific mechanism remains unclear. In this study, miR‐431‐5p was markedly downregulated in both gastric cancer (GC) tissues and plasma exosomes, and its expression were correlated negatively with LN metastasis and poor prognosis. Mechanistically, miR‐431‐5p weakens the TGF‐β1/SMAD2/3 signaling pathway by targeting ZEB1, thereby suppressing the secretion of VEGF‐A and ANG2, which in turn hinders angiogenesis, lymphangiogenesis, and lymph node (LN) metastasis in GC. Experiments using a popliteal LN metastasis model in BALB/c nude mice demonstrated that miR‐431‐5p significantly reduced popliteal LN metastasis. Additionally, miR‐431‐5p enhances the efficacy of anti‐PD1 treatment, particularly when combined with galunisertib, anti‐PD1 treatment showing a synergistic effect in inhibiting GC progression in C57BL/6 mice. Collectively, these findings suggest that miR‐431‐5p may modulate the TGF‐β1/SMAD2/3 pathways by targeting ZEB1 to impede GC progression, angiogenesis, and lymphangiogenesis, making it a promising therapeutic target for GC management.