The Wnt-ß-catenin pathway represses let-7 microRNA expression through transactivation of Lin28 to augment breast cancer stem cell expansion.
J Cell Sci
; 126(Pt 13): 2877-89, 2013 Jul 01.
Article
en En
| MEDLINE
| ID: mdl-23613467
ABSTRACT
Wnt signalling through ß-catenin and the lymphoid-enhancing factor 1/T-cell factor (LEF1/TCF) family of transcription factors maintains stem cell properties in both normal and malignant tissues; however, the underlying molecular pathway involved in this process has not been completely defined. Using a microRNA microarray screening assay, we identified let-7 miRNAs as downstream targets of the Wnt-ß-catenin pathway. Expression studies indicated that the Wnt-ß-catenin pathway suppresses mature let-7 miRNAs but not the primary transcripts, which suggests a post-transcriptional regulation of repression. Furthermore, we identified Lin28, a negative let-7 biogenesis regulator, as a novel direct downstream target of the Wnt-ß-catenin pathway. Loss of function of Lin28 impairs Wnt-ß-catenin-pathway-mediated let-7 inhibition and breast cancer stem cell expansion; enforced expression of let-7 blocks the Wnt-ß-catenin pathway-stimulated breast cancer stem cell phenotype. Finally, we demonstrated that the Wnt-ß-catenin pathway induces Lin28 upregulation and let-7 downregulation in both cancer samples and mouse tumour models. Moreover, the delivery of a modified lin28 siRNA or a let-7a agomir into the premalignant mammary tissues of MMTV-wnt-1 mice resulted in a complete rescue of the stem cell phenotype driven by the Wnt-ß-catenin pathway. These findings highlight a pivotal role for Lin28/let-7 in Wnt-ß-catenin-pathway-mediated cellular phenotypes. Thus, the Wnt-ß-catenin pathway, Lin28 and let-7 miRNAs, three of the most crucial stem cell regulators, connect in one signal cascade.
Palabras clave
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Células Madre Neoplásicas
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Transducción de Señal
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Regulación Neoplásica de la Expresión Génica
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Proteínas de Unión al ARN
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MicroARNs
/
Proteína Wnt1
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Beta Catenina
Tipo de estudio:
Prognostic_studies
Límite:
Animals
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Female
/
Humans
Idioma:
En
Revista:
J Cell Sci
Año:
2013
Tipo del documento:
Article
País de afiliación:
China