Inflammation and DNA Methylation-Dependent Down-Regulation of miR-34b-5p Mediates c-MYC Expression and CRL4DCAF4 E3 Ligase Activity in Colitis-Associated Cancer.
Am J Pathol
; 190(3): 674-688, 2020 03.
Article
em En
| MEDLINE
| ID: mdl-31972160
ABSTRACT
miRNAs, a well-known group of noncoding RNAs, contribute to the pathogenesis of multiple diseases, including colitis-associated cancer (CAC). Our recent findings indicate that proinflammatory cytokines up-regulate c-MYC level, which subsequently activates cullin 4A and 4B (CUL4A/4B) and CRL4DCAF4 E3 ligases and promotes ubiquitination of suppression of tumorigenicity 7 in CAC. Herein, we identified and proved that miR-34b-5p can directly target c-MYC. In vitro oncogenic phenotype analyses and in vivo tumor formation assay indicated that miR-34b-5p overexpression could markedly decrease cell proliferation, colony formation, cell invasion, and tumor volumes. Overexpression of c-MYC in vitro could reverse the oncogenic phenotypes caused by miR-34b-5p up-regulation. In addition, the down-regulation of miR-34b-5p in CAC was dependent on the coregulation of the inflammatory microenvironment and DNA methylation. Collectively, our findings demonstrate that intracellular inflammation and DNA hypermethylation suppress miR-34b-5p expression, which limits its inhibitory effect on c-MYC and initiates the downstream events, including the induction of CRL4DCAF4 E3 ligase activity. The activated CRL4DCAF4 E3 ligase ubiquitinates suppression of tumorigenicity 7 and results in its degradation, eventually leading to the CAC tumorigenesis.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Proteínas Proto-Oncogênicas c-myc
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Colite
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Neoplasias do Colo
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MicroRNAs
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Ubiquitina-Proteína Ligases
Tipo de estudo:
Prognostic_studies
/
Risk_factors_studies
Limite:
Humans
Idioma:
En
Revista:
Am J Pathol
Ano de publicação:
2020
Tipo de documento:
Article
País de afiliação:
China