HIF-1É-regulated miR-1275 maintains stem cell-like phenotypes and promotes the progression of LUAD by simultaneously activating Wnt/ß-catenin and Notch signaling.
Theranostics
; 10(6): 2553-2570, 2020.
Article
em En
| MEDLINE
| ID: mdl-32194819
ABSTRACT
Rationale Cancer stem cells (CSCs) are considered to be essential for tumorigenesis, recurrence, and metastasis and therefore serve as a biomarker for tumor progression in diverse cancers. Recent studies have illustrated that specific miRNAs exhibit novel therapeutic potential by controlling CSC properties. miR-1275 is upregulated in lung adenocarcinoma (LUAD) and enhances its stemness. However, the underlying mechanisms have not been elucidated. Methods:
miRNA expression microarray of LUAD and adjacent nontumor tissues was used to identify miRNAs involved in LUAD malignant progression. miR-1275 expression level was determined using quantitative real-time PCR (RT-qPCR) and in situ hybridization (ISH), and its correlation with clinicopathological characteristics was analyzed in LUAD specimens. The upstream regulator of miR-1275 was validated by chromatin immunoprecipitation (ChIP). The biological functions and underlying mechanisms of miR-1275 were investigated both in vitro and in vivo.Results:
MiR-1275 was highly upregulated in lung cancer cell lines and LUAD tissues. Overexpression of miR-1275 in lung cancer patients was associated with shorter overall- and recurrence-free-survival. Proto-oncogene HIF-1É was identified as the transcription mediator of miR-1275. Activation of Wnt/ß-catenin and Notch signaling by miR-1275 was found to enhance the stemness of LUAD cells, while antagonizing miR-1275 or suppressing Wnt/ß-catenin and Notch pathways potently reversed miR-1275-induced pathway co-activation and stemness. Enhanced stemness dramatically promoted tumorigenicity, recurrence, and metastasis. miR-1275 directly targeted multiple antagonists of Wnt/ß-catenin and Notch pathways, including DKK3, SFRP1, GSK3ß, RUNX3, and NUMB, respectively, which resulted in signaling activation.Conclusions:
Our findings identified miR-1275 as a potential oncogene in LUAD that exerts its tumorigenic effect through co-activating Wnt/ß-catenin and Notch signaling pathways. Thus, HIF-1É-regulated miR-1275 might be a potential therapeutic target for LUAD.Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Neoplásicas
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MicroRNAs
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Subunidade alfa do Fator 1 Induzível por Hipóxia
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Adenocarcinoma de Pulmão
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Neoplasias Pulmonares
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Revista:
Theranostics
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China