Deletion of NEMO/IKKγ in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma
Deletion of NEMO/IKKγ in liver parenchymal cells causes steatohepatitis and hepatocellular carcinoma
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DOI：
10.1016/j.ccr.2006.12.016
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发表时间：
2007-02-01
期刊：
影响因子：
50.3
通讯作者：
Pasparakis, Manolis
中科院分区：
文献类型：
--
作者：
Luedde, Tom;Beraza, Naiara;Pasparakis, Manolis
IicB激酶（IKK）亚基NEMO/IKK γ对转录因子NF-κ B的激活至关重要，NF-κ B调节细胞对炎症的反应。NEMO在成人肝脏中的功能仍然难以捉摸。在这里，我们表明，消融NEMO在肝实质细胞引起自发发展的小鼠肝细胞癌。肿瘤发展之前是类似于人类非酒精性脂肪性肝炎（NASH）的慢性肝病。抗氧化剂治疗和FADD的基因消融表明，NEMO缺陷肝细胞的死亡受体介导的和氧化应激依赖性死亡触发了该模型中的疾病发病机制。这些结果表明，NEMO介导的肝细胞中NF-κ B活化具有防止脂肪性肝炎和肝细胞癌自发发展的重要生理功能，从而确定NEMO是肝脏中的肿瘤抑制因子。
The licB kinase (IKK) subunit NEMO/IKK gamma is essential for activation of the transcription factor NF-kappa B, which regulates cellular responses to inflammation. The function of NEMO in the adult liver remains elusive. Here we show that ablation of NEMO in liver parenchymal cells caused the spontaneous development of hepatocellular carcinoma in mice. Tumor development was preceded by chronic liver disease resembling human nonalcoholic steatohepatitis (NASH). Antioxidant treatment and genetic ablation of FADD demonstrated that death receptor-mediated and oxidative stress-dependent death of NEMO-deficient hepatocytes triggered disease pathogenesis in this model. These results reveal that NEMO-mediated NF-kappa B activation in hepatocytes has an essential physiological function to prevent the spontaneous development of steatohepatitis and hepatocellular carcinoma, identifying NEMO as a tumor suppressor in the liver.