Bak deficiency inhibits liver carcinogenesis: A causal link between apoptosis and carcinogenesis
Bak deficiency inhibits liver carcinogenesis: A causal link between apoptosis and carcinogenesis
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DOI：
10.1016/j.jhep.2012.01.027
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发表时间：
2012-07-01
影响因子：
25.7
通讯作者：
Takehara, Tetsuo
中科院分区：
文献类型：
--
作者：
Hikita, Hayato;Kodama, Takahiro;Takehara, Tetsuo
背景与目的：肝细胞凋亡是慢性肝病（包括病毒性肝炎和脂肪性肝炎）的一个重要特征。先前的研究表明，Bcl-2家族蛋白Mcl-1的缺失导致小鼠肝细胞凋亡增加和肝肿瘤的发展。由于Mcl-1不仅抑制凋亡的线粒体途径，而且还可以抑制细胞周期进程和促进DNA修复，因此Mcl-1的肿瘤抑制作用是否通过预防凋亡介导还有待证明。我们检查了肝细胞特异性敲除（KO）Mcl-1或Bcl-xL的肝脏中的肝肿瘤发展、纤维化和氧化应激，肝细胞凋亡的另一个关键拮抗剂。我们还研究了额外的KO的巴克，一个下游分子的Mcl-1对细胞凋亡，但不是细胞周期或DNA损伤途径，对肿瘤的发展，肝细胞凋亡，和inflammation.Results的影响：Bcl-xL KO导致高发病率的肝肿瘤在1.5岁的小鼠，类似于Mcl-1 KO。Bcl-xL-或Mcl-1-缺陷的肝脏在早6周龄时就表现出比野生型肝脏更高水平的TNF-α产生和氧化应激，并在1.5岁时表现出氧化DNA损伤。删除的巴克显着抑制肝细胞凋亡的Mcl-1基因敲除小鼠，降低肝癌的发病率，同时减少TNF-α的生产，氧化应激，氧化DNA损伤在非癌livers.Conclusions：我们的研究结果强烈表明，慢性增加肝细胞凋亡是致癌的，并提供遗传证据，细胞凋亡的抑制可能会抑制慢性肝病的肝癌发生。(C)2012年欧洲肝脏研究协会。Elsevier B. V.出版，保留所有权利。
Background & Aims: Hepatocyte apoptosis is a key feature of chronic liver disease including viral hepatitis and steatohepatitis. A previous study demonstrated that absence of the Bcl-2 family protein Mcl-1 led to increased hepatocyte apoptosis and development of liver tumors in mice. Since Mcl-1 not only inhibits the mitochondrial pathway of apoptosis but can also inhibit cell cycle progression and promote DNA repair, it remains to be proven whether the tumor suppressive effects of Mcl-1 are mediated by prevention of apoptosis.Methods: We examined liver tumor development, fibrogenesis, and oxidative stress in livers of hepatocyte-specific knockout (KO) of Mcl-1 or Bcl-xL, another key antagonist of apoptosis in hepatocytes. We also examined the impact of additional KO of Bak, a downstream molecule of Mcl-1 towards apoptosis but not the cell cycle or DNA damage pathway, on tumor development, hepatocyte apoptosis, and inflammation.Results: Bcl-xL KO led to a high incidence of liver tumors in 1.5-year-old mice, similar to Mcl-1 KO. Bcl-xL- or Mcl-1-deficient livers showed higher levels of TNF-alpha production and oxidative stress than wild-type livers at as early as 6 weeks of age and oxidative DNA damage at 1.5 years. Deletion of Bak significantly inhibited hepatocyte apoptosis in Mcl-1 KO mice and reduced the incidence of liver cancer, coinciding with reduction of TNF-alpha production, oxidative stress, and oxidative DNA damage in non-cancerous livers.Conclusions: Our findings strongly suggest that chronically increased apoptosis in hepatocytes is carcinogenic and offer genetic evidence that inhibition of apoptosis may suppress liver carcinogenesis in chronic liver disease. (C) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.