WWOX controls hepatic HIF1α to suppress hepatocyte proliferation and neoplasia.
Cell Death Dis
; 9(5): 511, 2018 05 01.
Article
en En
| MEDLINE
| ID: mdl-29724996
ABSTRACT
Liver cancer is one of the most lethal malignancies with very poor prognosis once diagnosed. The most common form of liver cancer is hepatocellular carcinoma (HCC). The WW domain-containing oxidoreductase (WWOX) is a large gene that is often perturbed in a wide variety of tumors, including HCC. WWOX has been shown to act as a tumor suppressor modulating cellular metabolism via regulating hypoxia-inducible factor 1α (HIF-1α) levels and function. Given that WWOX is commonly inactivated in HCC, we set to determine whether specific targeted deletion of murine Wwox affects liver biology and HCC development. WWOX liver-specific knockout mice (Wwox ΔHep ) showed more potent liver regeneration potential and enhanced proliferation as compared with their control littermates. Moreover, WWOX deficiency in hepatocytes combined with diethylnitrosamine treatment increased the tumor burden, which was associated with increased HIF1α levels and target gene transactivation. Inhibition of HIF1α by systemic treatment with digoxin significantly delayed HCC formation. Our work suggests that WWOX inactivation has a central role in promoting HCC through rewiring of cellular metabolism and modulating proliferation.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Contexto en salud:
1_ASSA2030
Problema de salud:
1_doencas_nao_transmissiveis
Asunto principal:
Regulación Neoplásica de la Expresión Génica
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Carcinoma Hepatocelular
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Proteínas Supresoras de Tumor
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Subunidad alfa del Factor 1 Inducible por Hipoxia
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Oxidorreductasa que Contiene Dominios WW
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Neoplasias Hepáticas
Tipo de estudio:
Etiology_studies
/
Prognostic_studies
Idioma:
En
Revista:
Cell Death Dis
Año:
2018
Tipo del documento:
Article
País de afiliación:
Israel