ß-catenin-activated hepatocellular carcinomas are addicted to fatty acids.
Gut
; 68(2): 322-334, 2019 02.
Article
em En
| MEDLINE
| ID: mdl-29650531
ABSTRACT
OBJECTIVES:
CTNNB1-mutated hepatocellular carcinomas (HCCs) constitute a major part of human HCC and are largely inaccessible to target therapy. Yet, little is known about the metabolic reprogramming induced by ß-catenin oncogenic activation in the liver. We aimed to decipher such reprogramming and assess whether it may represent a new avenue for targeted therapy of CTNNB1-mutated HCC.DESIGN:
We used mice with hepatocyte-specific oncogenic activation of ß-catenin to evaluate metabolic reprogramming using metabolic fluxes on tumourous explants and primary hepatocytes. We assess the role of Pparα in knock-out mice and analysed the consequences of fatty acid oxidation (FAO) using etomoxir. We explored the expression of the FAO pathway in an annotated human HCC dataset.RESULTS:
ß-catenin-activated HCC were not glycolytic but intensively oxidised fatty acids. We found that Pparα is a ß-catenin target involved in FAO metabolic reprograming. Deletion of Pparα was sufficient to block the initiation and progression of ß-catenin-dependent HCC development. FAO was also enriched in human CTNNB1-mutated HCC, under the control of the transcription factor PPARα.CONCLUSIONS:
FAO induced by ß-catenin oncogenic activation in the liver is the driving force of the ß-catenin-induced HCC. Inhibiting FAO by genetic and pharmacological approaches blocks HCC development, showing that inhibition of FAO is a suitable therapeutic approach for CTNNB1-mutated HCC.Palavras-chave
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Base de dados:
MEDLINE
Assunto principal:
Carcinoma Hepatocelular
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Beta Catenina
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Ácidos Graxos
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Neoplasias Hepáticas
Idioma:
En
Ano de publicação:
2019
Tipo de documento:
Article