Use of miR145 and testicular nuclear receptor 4 inhibition to reduce chemoresistance to docetaxel in prostate cancer.
Oncol Rep
; 45(3): 963-974, 2021 03.
Article
em En
| MEDLINE
| ID: mdl-33650661
ABSTRACT
The human testicular nuclear receptor 4 (TR4) is a critical regulatory gene for the progression of prostate cancer (PCa). Although it has been revealed that TR4 causes chemoresistance in PCa via the activation of octamerbinding transcription factor 4 (OCT4), the detailed mechanism remains unexplored. In the present study, it was revealed that inhibition of TR4 by shRNA in PCa enhanced the sensitivity to docetaxel in vitro and in vivo. TR4 induced the downregulation of miR145 by directly binding it to the promoter of miR145, which was confirmed by chromatin immunoprecipitation analysis and luciferase assay. The overexpression of miR145 suppressed both the chemoresistance and the expression of OCT4 mRNA and protein. Additionally, the TR4 shRNA mediated resensitization to docetaxel, along with the downregulated expression of OCT4, were reversed by the concurrent inhibition of miR145. The luciferase assay revealed that the activity of the wildtype OCT4 3' untranslated region reporter was suppressed. This suppression diminished when the miR145 response element mutated. These findings suggest an undescribed regulatory pathway in PCa, by which TR4 directly suppressed the expression of miR145, thereby inhibiting its direct target OCT4, leading to the promotion of chemoresistance in PCa.
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Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Neoplasias da Próstata
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Receptores dos Hormônios Tireóideos
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Receptores de Esteroides
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Resistencia a Medicamentos Antineoplásicos
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MicroRNAs
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Docetaxel
Idioma:
En
Ano de publicação:
2021
Tipo de documento:
Article