The lysyl oxidases LOX and LOXL2 are necessary and sufficient to repress E-cadherin in hypoxia: insights into cellular transformation processes mediated by HIF-1.
J Biol Chem
; 285(9): 6658-69, 2010 Feb 26.
Article
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| MEDLINE
| ID: mdl-20026874
ABSTRACT
Hypoxia has been shown to promote tumor metastasis and lead to therapy resistance. Recent work has demonstrated that hypoxia represses E-cadherin expression, a hallmark of epithelial to mesenchymal transition, which is believed to amplify tumor aggressiveness. The molecular mechanism of E-cadherin repression is unknown, yet lysyl oxidases have been implicated to be involved. Gene expression of lysyl oxidase (LOX) and the related LOX-like 2 (LOXL2) is strongly induced by hypoxia. In addition to the previously demonstrated LOX, we characterize LOXL2 as a direct transcriptional target of HIF-1. We demonstrate that activation of lysyl oxidases is required and sufficient for hypoxic repression of E-cadherin, which mediates cellular transformation and takes effect in cellular invasion assays. Our data support a molecular pathway from hypoxia to cellular transformation. It includes up-regulation of HIF and subsequent transcriptional induction of LOX and LOXL2, which repress E-cadherin and induce epithelial to mesenchymal transition. Lysyl oxidases could be an attractive molecular target for cancers of epithelial origin, in particular because they are partly extracellular.
Texto completo:
1
Banco de datos:
MEDLINE
Asunto principal:
Cadherinas
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Transformación Celular Neoplásica
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Subunidad alfa del Factor 1 Inducible por Hipoxia
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Aminoácido Oxidorreductasas
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Proteína-Lisina 6-Oxidasa
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Hipoxia
Límite:
Humans
Idioma:
En
Año:
2010
Tipo del documento:
Article