Astrocyte elevated gene-1 promotes hepatocarcinogenesis: novel insights from a mouse model.
Hepatology
; 56(5): 1782-91, 2012 Nov.
Article
en En
| MEDLINE
| ID: mdl-22689379
ABSTRACT
UNLABELLED Astrocyte elevated gene-1 (AEG-1) is a key contributor to hepatocellular carcinoma (HCC) development and progression. To enhance our understanding of the role of AEG-1 in hepatocarcinogenesis, a transgenic mouse with hepatocyte-specific expression of AEG-1 (Alb/AEG1) was developed. Treating Alb/AEG-1, but not wild-type (WT) mice, with N-nitrosodiethylamine resulted in multinodular HCC with steatotic features and associated modulation of expression of genes regulating invasion, metastasis, angiogenesis, and fatty acid synthesis. Hepatocytes isolated from Alb/AEG-1 mice displayed profound resistance to chemotherapeutics and growth factor deprivation with activation of prosurvival signaling pathways. Alb/AEG-1 hepatocytes also exhibited marked resistance toward senescence, which correlated with abrogation of activation of a DNA damage response. Conditioned media from Alb/AEG-1 hepatocytes induced marked angiogenesis with elevation in several coagulation factors. Among these factors, AEG-1 facilitated the association of factor XII (FXII) messenger RNA with polysomes, resulting in increased translation. Short interfering RNA-mediated knockdown of FXII resulted in profound inhibition of AEG-1-induced angiogenesis. CONCLUSION:
We uncovered novel aspects of AEG-1 functions, including induction of steatosis, inhibition of senescence, and activation of the coagulation pathway to augment aggressive hepatocarcinogenesis. The Alb/AEG-1 mouse provides an appropriate model to scrutinize the molecular mechanism of hepatocarcinogenesis and to evaluate the efficacy of novel therapeutic strategies targeting HCC.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Moléculas de Adhesión Celular
/
Transformación Celular Neoplásica
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Carcinoma Hepatocelular
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Modelos Animales de Enfermedad
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Neoplasias Hepáticas
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Neovascularización Patológica
Tipo de estudio:
Prognostic_studies
Idioma:
En
Revista:
Hepatology
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos