Orejuela Diana, Jorquera Rossana, Bergeron Anne, Finegold Milton J, Tanguay Robert M
Laboratory of Cell and Developmental Genetics, Department of Medicine and CREFSIP, Pav. Marchand, Université Laval, Québec, Canada G1K 7P4.
J Hepatol. 2008 Feb;48(2):308-17. doi: 10.1016/j.jhep.2007.09.014. Epub 2007 Dec 3.
BACKGROUND/AIMS: The AKT survival pathway is involved in a wide variety of human cancers. We investigated the implication of this pathway in hereditary tyrosinemia type 1 (HT1), a metabolic disease exhibiting hepatocellular carcinoma (HCC), despite treatment with 2-(2-nitro-4-trifluoromethylbenzoyl)-1,3-cyclohexadione (NTBC) which prevents liver damage. HT1 is an autosomal recessive disorder caused by accumulation of toxic metabolites due to a deficiency in fumarylacetoacetate hydrolase (FAH), the last enzyme in the catabolism of tyrosine.
NTBC withdrawal in the murine fah(-/-) knockout model was used to analyze in vivo the correlation between pathophysiological, biochemical and histological features consistent with hepatocarcinogenesis and activation of the AKT survival pathway.
The HT1 stress initiated by NTBC discontinuation causes a progressive increase of liver and kidney pathophysiology. A stable activation of the AKT survival pathway is observed in the liver but not in kidneys of fah(-/-) mice. Hepatic survival is reinforced by inhibition of mitochondrial-mediated apoptosis through inactivation of Bad and induction of BCl-X(L) and BCl-2.
The chronic stress induced by liver disease in HT1 activates the AKT survival signal and inhibits intrinsic apoptosis to confer cell death resistance in vivo and favor hepatocarcinogenesis.
背景/目的：AKT生存信号通路参与多种人类癌症。我们研究了该通路在1型遗传性酪氨酸血症（HT1）中的作用，HT1是一种代谢性疾病，尽管使用2-(2-硝基-4-三氟甲基苯甲酰基)-1,3-环己二酮（NTBC）治疗可预防肝损伤，但仍会发生肝细胞癌（HCC）。HT1是一种常染色体隐性疾病，由于酪氨酸分解代谢的最后一种酶——富马酰乙酰乙酸水解酶（FAH）缺乏，导致有毒代谢产物积累所致。
在小鼠fah(-/-)基因敲除模型中停用NTBC，以在体内分析与肝癌发生和AKT生存信号通路激活相一致的病理生理、生化和组织学特征之间的相关性。
停用NTBC引发的HT1应激导致肝脏和肾脏病理生理逐渐加重。在fah(-/-)小鼠的肝脏中观察到AKT生存信号通路的稳定激活，而在肾脏中未观察到。通过使Bad失活以及诱导Bcl-X(L)和Bcl-2，抑制线粒体介导的凋亡，增强了肝脏的生存能力。
HT1中肝脏疾病诱导的慢性应激激活了AKT生存信号，并抑制了内源性凋亡，从而在体内赋予细胞抗死亡能力，并促进肝癌发生。
