MicroRNA-431-5p inhibits angiogenesis, lymphangiogenesis, and lymph node metastasis by affecting TGF-ß1/SMAD2/3 signaling via ZEB1 in gastric cancer.
Mol Carcinog
; 63(7): 1378-1391, 2024 Jul.
Article
em En
| MEDLINE
| ID: mdl-38656643
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-ß1/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-ß1/SMAD2/3 pathways by targeting ZEB1 to impede GC progression, angiogenesis, and lymphangiogenesis, making it a promising therapeutic target for GC management.
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias Gástricas
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Transdução de Sinais
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Regulação Neoplásica da Expressão Gênica
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MicroRNAs
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Linfangiogênese
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Proteína Smad2
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Proteína Smad3
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Fator de Crescimento Transformador beta1
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Homeobox 1 de Ligação a E-box em Dedo de Zinco
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Metástase Linfática
Limite:
Animals
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Female
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Humans
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Male
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Middle aged
Idioma:
En
Ano de publicação:
2024
Tipo de documento:
Article