Kindlin-2-miR-1258-TCF4 feedback loop promotes hepatocellular carcinoma invasion and metastasis.
J Gastroenterol
; 57(5): 372-386, 2022 05.
Article
em En
| MEDLINE
| ID: mdl-35244769
ABSTRACT
BACKGROUND:
Upregulated Kindlin-2 expression in hepatocellular carcinoma (HCC) correlates with metastasis and poor prognosis. In this study, we investigated the molecular mechanism of Kindlin-2 in HCC.METHODS:
Kindlin-2 downstream pathways were explored through microRNA sequencing. The Kindlin-2-miR-1258-TCF4 axis was verified using bisulfite sequencing, a luciferase reporter assay, quantitative real-time PCR, and rescue assays. Binding of TCF4 to the Kindlin-2 promoter was confirmed by promoter activity analysis and chromatin immunoprecipitation.RESULTS:
MiRNA sequencing identified miR-1258 as a downstream effector of Kindlin-2. MiR-1258 expression was increased following Kindlin-2 knockdown and decreased after Kindlin-2 overexpression. Next, we identified transcription factor 7 like 2 (TCF7L2 or TCF4) as a target of miR-1258 and found that Kindlin-2 upregulated TCF4 expression by epigenetically suppressing miR-1258 in HCC. Furthermore, our results suggest that TCF4 binds to the Kindlin-2 promotor to enhance its transcription. Therefore, Kindlin-2-miR-1258-TCF4 interaction creates a positive feedback loop. Functional assays and animal experiments demonstrated critical roles of miR-1258 and TCF4 in HCC cell migration in vitro and HCC metastasis in vivo. In HCC tissues, Kindlin-2 expression correlated negatively with miR-1258 expression and positively with TCF4 expression. Meanwhile, miR-1258 expression correlated negatively with TCF4 expression.CONCLUSIONS:
This study illustrates a novel integrin-independent signaling pathway, Kindlin-2-miR-1258-TCF4, that regulates HCC invasion and metastasis and identifies Kindlin-2 as a promising therapeutic target in HCC.Palavras-chave
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Carcinoma Hepatocelular
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MicroRNAs
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Fator de Transcrição 4
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Neoplasias Hepáticas
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Proteínas de Membrana
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Proteínas de Neoplasias
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2022
Tipo de documento:
Article