In:
Gut, BMJ, Vol. 68, No. 2 ( 2019-02), p. 322-334
Abstract:
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 β-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 β-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 β-catenin-activated HCC were not glycolytic but intensively oxidised fatty acids. We found that Pparα is a β-catenin target involved in FAO metabolic reprograming. Deletion of Pparα was sufficient to block the initiation and progression of β-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 β-catenin oncogenic activation in the liver is the driving force of the β-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.
Type of Medium:
Online Resource
ISSN:
0017-5749
,
1468-3288
DOI:
10.1136/gutjnl-2017-315448
DOI:
10.1136/gutjnl-2017-315448.supp1
DOI:
10.1136/gutjnl-2017-315448.supp2
DOI:
10.1136/gutjnl-2017-315448.supp3
DOI:
10.1136/gutjnl-2017-315448.supp4
DOI:
10.1136/gutjnl-2017-315448.supp5
DOI:
10.1136/gutjnl-2017-315448.supp6
Language:
English
Publisher:
BMJ
Publication Date:
2019
detail.hit.zdb_id:
1492637-4
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