β-catenin-activated hepatocellular carcinomas are addicted to fatty acids
β-catenin-activated hepatocellular carcinomas are addicted to fatty acids
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DOI：
10.1136/gutjnl-2017-315448
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发表时间：
2019-02-01
期刊：
影响因子：
24.5
通讯作者：
Bossard, Pascale
中科院分区：
文献类型：
--
作者：
Senni, Nadia;Savall, Mathilde;Bossard, Pascale
目的 CTNNB1 突变的肝细胞癌 (HCC) 构成人类 HCC 的主要部分，并且基本上无法进行靶向治疗。然而，人们对肝脏中β-连环蛋白致癌激活诱导的代谢重编程知之甚少。我们的目的是破译这种重编程，并评估它是否可能代表 CTNNB1 突变 HCC 靶向治疗的新途径。设计我们使用具有肝细胞特异性致癌激活 β-连环蛋白的小鼠，利用肿瘤外植体和原代肝细胞上的代谢流来评估代谢重编程。我们评估了 PPAR α 在基因敲除小鼠中的作用，并使用依托莫昔分析了脂肪酸氧化 (FAO) 的后果。我们探索了带注释的人类 HCC 数据集中FAO 途径的表达。结果 β-连环蛋白激活的 HCC 不是糖酵解脂肪酸，而是强烈氧化的脂肪酸。我们发现 PPAR α 是参与 FAO 代谢重编程的 β-连环蛋白靶标。 PPAR α 的缺失足以阻止 β-连环蛋白依赖性 HCC 发展的启动和进展。在转录因子PPARα的控制下，FAO也在人类CTNNB1突变的HCC中富集。 结论 肝脏中β-连环蛋白致癌激活诱导的FAO是β-连环蛋白诱导的HCC的驱动力。通过遗传和药理学方法抑制FAO可阻止HCC的发展，表明抑制FAO是CTNNB1突变HCC的合适治疗方法。
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 beta-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 beta-catenin to evaluate metabolic reprogramming using metabolic fluxes on tumourous explants and primary hepatocytes. We assess the role of PPAR alpha 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 beta-catenin-activated HCC were not glycolytic but intensively oxidised fatty acids. We found that PPAR alpha is a beta-catenin target involved in FAO metabolic reprograming. Deletion of PPAR alpha was sufficient to block the initiation and progression of beta-catenin-dependent HCC development. FAO was also enriched in human CTNNB1-mutated HCC, under the control of the transcription factor PPAR alpha.Conclusions FAO induced by beta-catenin oncogenic activation in the liver is the driving force of the beta-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.