Quantitatively controlling expression of miR-17~92 determines colon tumor progression in a mouse tumor model.
Am J Pathol
; 184(5): 1355-68, 2014 May.
Article
em En
| MEDLINE
| ID: mdl-24681249
ABSTRACT
The miRNA cluster miR-17~92 targets mRNAs involved in distinct pathways that either promote or inhibit tumor progression. However, the cellular and molecular mechanisms underlying miR-17~92 cluster-mediated protumorigenic or anti-tumorigenic effects have not been studied. Herein, we determined that inhibition of colon cancer progression is dictated by quantitatively controlling expression of the miR-17~92 cluster. miR-19 in the context of the miR-17~92 cluster at medium levels promoted tumor metastasis through induction of Wnt/ß-catenin-mediated epithelial-mesenchymal transition by targeting to the tumor-suppressor gene, PTEN. However, higher levels of the miR-17~92 cluster switched from PTEN to oncogenes, including Ctnnb1 (ß-catenin) via miR-18a, which resulted in inhibition of tumor growth and metastasis. However, overexpression of Ctnnb1in tumor cells with high-level miR-17~92 did not lead to an increase in the levels of ß-catenin protein, suggesting that other factors regulated by higher levels of miR-17~92 might also contribute to inhibition of tumor growth and metastasis. Those unidentified factors may negatively regulate the production of ß-catenin protein. Collectively, the data presented in this study revealed that higher levels of miR-17~92 were a critical negative regulator for activation of the Wnt/ß-catenin pathway and could have a potential therapeutic application.
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Regulação Neoplásica da Expressão Gênica
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Neoplasias do Colo
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Progressão da Doença
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MicroRNAs
Tipo de estudo:
Prognostic_studies
Limite:
Animals
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Female
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Humans
Idioma:
En
Ano de publicação:
2014
Tipo de documento:
Article