Timeless-Stimulated miR-5188-FOXO1/ß-Catenin-c-Jun Feedback Loop Promotes Stemness via Ubiquitination of ß-Catenin in Breast Cancer.
Mol Ther
; 28(1): 313-327, 2020 01 08.
Article
en En
| MEDLINE
| ID: mdl-31604679
ABSTRACT
MicroRNAs (miRNAs) play an essential role in the self-renewal of breast cancer stem cells (BCCs). Our study aimed to clarify the role of proto-oncogene c-Jun-regulated miR-5188 in breast cancer progression and its association with Timeless-mediated cancer stemness. In the present study, we showed that miR-5188 exerted an oncogenic effect by inducing breast cancer stemness, proliferation, metastasis, and chemoresistance in vitro and in vivo. The mechanistic analysis demonstrated that miR-5188 directly targeted FOXO1, which interacted with ß-catenin in the cytoplasm, facilitated ß-catenin degradation, and impaired the nuclear accumulation of ß-catenin, thus stimulating the activation of known Wnt targets, epithelial-mesenchymal transition (EMT) markers, and key regulators of cancer stemness. Moreover, miR-5188 potentiated Wnt/ß-catenin/c-Jun signaling to promote breast cancer progression. Interestingly, c-Jun enhanced miR-5188 transcription to form a positive regulatory loop, and Timeless interacted with Sp1/c-Jun to induce miR-5188 expression by promoting c-Jun-mediated transcription, which further activated miR-5188-FOXO1/ß-catenin-c-Jun loop and facilitated breast cancer progression. Importantly, miR-5188 was upregulated in breast cancer and was positively correlated with poor patient prognosis. This study identifies miR-5188 as a novel oncomiR and provides a new theoretical basis for the clinical use of miR-5188 antagonists in the treatment of breast cancer.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Neoplasias de la Mama
/
Proteínas Proto-Oncogénicas c-jun
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MicroARNs
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Beta Catenina
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Ubiquitinación
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Proteína Forkhead Box O1
Tipo de estudio:
Prognostic_studies
Límite:
Adult
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Animals
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Female
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Humans
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Male
/
Middle aged
Idioma:
En
Revista:
Mol Ther
Asunto de la revista:
BIOLOGIA MOLECULAR
/
TERAPEUTICA
Año:
2020
Tipo del documento:
Article