Lactate promoted cisplatin resistance in NSCLC by modulating the m6A modification-mediated FOXO3/MAGI1-IT1/miR-664b-3p/IL-6R axis.
Neoplasia
; 48: 100960, 2024 02.
Article
em En
| MEDLINE
| ID: mdl-38184887
ABSTRACT
BACKGROUND:
Cisplatin resistance is one of the major obstacles in non-small cell lung cancer (NSCLC) treatment. Intriguingly, elevated lactate levels were observed in cisplatin-resistant cells, which spurred further investigation into their underlying biological mechanisms.METHODS:
Lactate levels were measured by lactate detection kit. Cisplatin-resistance NSCLC cells were established using progressive concentration of cisplatin. Cell viability, proliferation, and apoptosis were detected by CCK-8, EdU, and flow cytometry, respectively. Cell proliferation in vivo was determined by immunohistochemistry of Ki67 and apoptotic cells were calculated by the TUNEL. MeRIP-PCR was used to measure FOXO3 m6A levels. The interactions of genes were analyzed via RIP, ChIP, Dual-luciferase reporter, and RNA pull-down, respectively.RESULTS:
Elevated lactate levels were observed in both NSCLC patients and cisplatin-resistance cells. Lactate treatment increased cisplatin-resistance cell viability in vitro and promoted tumor growth in vivo. Mechanistically, lactate downregulated FOXO3 by YTHDF2-mediated m6A modification. FOXO3 transcriptionally reduced MAGI1-IT1 expression. FOXO3 overexpression inhibited the lactate-induced promotion of cisplatin resistance in NSCLC, which were reversed by MAGI1-IT1 overexpression. MAGI1-IT1 and IL6R competitively bound miR-664b-3p. FOXO3 overexpression or MAGI1-IT1 knockdown repressed lactate-mediated cisplatin resistance in vivo.CONCLUSION:
Lactate promoted NSCLC cisplatin resistance through regulating FOXO3/MAGI1-IT1/miR-664b-3p/IL6R axis in YTHDF2-mediated m6A modification.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Adenina
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Carcinoma Pulmonar de Células não Pequenas
/
MicroRNAs
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Proteína Forkhead Box O3
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Neoplasias Pulmonares
Limite:
Humans
Idioma:
En
Revista:
Neoplasia
Assunto da revista:
NEOPLASIAS
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
China