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首页> 外文期刊>Cancer Cell >Inactivation of the Deubiquitinase CYLD in Hepatocytes Causes Apoptosis, Inflammation, Fibrosis, and Cancer
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Inactivation of the Deubiquitinase CYLD in Hepatocytes Causes Apoptosis, Inflammation, Fibrosis, and Cancer

机译：肝细胞中去泛素化酶CYLD的失活导致细胞凋亡，炎症，纤维化和癌症。

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The tumor suppressor cylindromatosis (CYLD) inhibits the NFκB and mitogen-activated protein kinase (MAPK) activation pathways by deubiquitinating upstream regulatory factors. Here we show that liver-specific disruption of CYLD triggers hepatocyte cell death in the periportal area via spontaneous and chronic activation of TGF-β activated kinase 1 (TAK1) and c-Jun N-terminal kinase (JNK). This is followed by hepatic stellate cell and Kupffer cell activation, which promotes progressive fibrosis, inflammation, tumor necrosis factor (TNF) production, and expansion of hepatocyte apoptosis toward the central veins. At later stages, compensatory proliferation results in the development of cancer foci featuring re-expression of oncofetal hepatic and stem cell-specific genes. The results demonstrate that, in the liver, CYLD acts as an important regulator of hepatocyte homeostasis, protecting cells from spontaneous apoptosis by preventing uncontrolled TAK1 and JNK activation.
机译：肿瘤抑制圆柱体病（CYLD）通过去泛素化上游调节因子来抑制NFκB和有丝分裂原激活的蛋白激酶（MAPK）激活途径。在这里，我们显示CYLD的肝脏特异性破坏通过TGF-β活化激酶1（TAK1）和c-Jun N末端激酶（JNK）的自发和慢性激活触发了肝周区域肝细胞死亡。随后是肝星状细胞和库普弗细胞活化，从而促进进行性纤维化，炎症，肿瘤坏死因子（TNF）的产生，以及肝细胞向中央静脉的凋亡扩展。在以后的阶段，代偿性增殖导致癌灶的发展，其特征是癌胚肝和干细胞特异性基因的重新表达。结果表明，在肝脏中，CYLD是肝细胞稳态的重要调节剂，可通过防止不受控制的TAK1和JNK活化来保护细胞免于自发凋亡。

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