The Third Department of Surgery, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Hebei Key Laboratory of Precision Diagnosis and Comprehensive Treatment of Gastric Cancer, Shijiazhuang, Hebei, China.
Mol Carcinog. 2024 Jul;63(7):1378-1391. doi: 10.1002/mc.23731. Epub 2024 Apr 24.
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.
越来越多的证据表明淋巴管生成在淋巴转移中起着至关重要的作用，导致肿瘤免疫耐受。然而，具体的机制尚不清楚。在这项研究中，miR-431-5p 在胃癌组织和血浆外泌体中均显著下调，其表达与 LN 转移和不良预后呈负相关。在机制上，miR-431-5p 通过靶向 ZEB1 减弱 TGF-β1/SMAD2/3 信号通路，从而抑制 VEGF-A 和 ANG2 的分泌，进而阻碍胃癌中的血管生成、淋巴管生成和淋巴结转移。在 BALB/c 裸鼠的隐窝淋巴结转移模型实验中，miR-431-5p 显著减少了隐窝淋巴结转移。此外，miR-431-5p 增强了抗 PD1 治疗的效果，特别是与 galunisertib 联合使用时，抗 PD1 治疗在抑制 C57BL/6 小鼠的 GC 进展方面具有协同作用。综上所述，这些发现表明，miR-431-5p 通过靶向 ZEB1 调节 TGF-β1/SMAD2/3 通路，阻碍 GC 的进展、血管生成和淋巴管生成，使其成为 GC 治疗的有前途的治疗靶点。
