4F2hc-silencing impairs tumorigenicity of HeLa cells via modulation of galectin-3 and ß-catenin signaling, and MMP-2 expression.
Biochim Biophys Acta
; 1833(9): 2045-56, 2013 Sep.
Article
em En
| MEDLINE
| ID: mdl-23651923
ABSTRACT
4F2hc is a type-II glycoprotein whose covalent-bound association with one of several described light chains yields a heterodimer mainly involved in large neutral amino acid transport. Likewise, it is well known that the heavy chain interacts with ß-integrins mediating integrin-dependent events such as survival, proliferation, migration and even transformation. 4F2hc is a ubiquitous protein whose overexpression has been related to tumor development and progression. Stable silencing of 4F2hc in HeLa cells using an artificial miRNA impairs in vivo tumorigenicity and leads to an ineffective proliferation response to mitogens. 4F2hc colocalizes with ß1-integrins and CD147, but this interaction does not occur in lipid rafts in HeLa cells. Moreover, silenced cells present defects in integrin- (FAK, Akt and ERK1/2) and hypoxia-dependent signaling, and reduced expression/activity of MMP-2. These alterations seem to be dependent on the inappropriate formation of CD147/4F2hc/ß1-integrin heterocomplexes on the cell surface, arising when CD147 cannot interact with 4F2hc. Although extracellular galectin-3 accumulates due to the decrease in MMP-2 activity, galectin-3 signaling events are blocked due to an impaired interaction with 4F2hc, inducing an increased degradation of ß-catenin. Furthermore, cell motility is compromised after protein silencing, suggesting that 4F2hc is related to tumor invasion by facilitating cell motility. Therefore, here we propose a molecular mechanism by which 4F2hc participates in tumor progression, favoring first steps of epithelial-mesenchymal transition by inhibition of ß-catenin proteasomal degradation through Akt/GSK-3ß signaling and enabling cell motility.
Texto completo:
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Base de dados:
MEDLINE
Assunto principal:
Regulação Enzimológica da Expressão Gênica
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Regulação Neoplásica da Expressão Gênica
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Metaloproteinase 2 da Matriz
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Sistema de Sinalização das MAP Quinases
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Inativação Gênica
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Cadeia Pesada da Proteína-1 Reguladora de Fusão
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Galectina 3
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Beta Catenina
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Neoplasias Experimentais
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2013
Tipo de documento:
Article