6月12日,，Cancer Cell雜志報道了去泛素化酶,，圓柱瘤病（CYLD）腫瘤抑制因子的失活可引發(fā)肝細(xì)胞的凋亡,、炎癥,、纖維化和癌癥。圓柱瘤?。–YLD）腫瘤抑制因子通過去泛素化上游因子,，抑制NFκB和有絲分裂原活化蛋白激酶（MAPK）活化途徑,。

本研究顯示，肝特異性阻斷CYLD通過自發(fā)的或慢性激活TGF-β活化激酶1（TAK1）和c-Jun N末端激酶（JNK）觸發(fā)了肝門靜脈周邊區(qū)域肝細(xì)胞的死亡,。隨后,，肝星形細(xì)胞和Kupper細(xì)胞活化，進(jìn)而促進(jìn)進(jìn)行性肝纖維化,、炎癥,、腫瘤壞死因子（TNF）產(chǎn)生，以及肝細(xì)胞凋亡朝向中央靜脈的擴(kuò)散,。在晚些階段,，補(bǔ)償性增殖導(dǎo)致癌性中心的產(chǎn)生。這些癌性中心特征性地重新表達(dá)癌胚肝細(xì)胞及干細(xì)胞特異性基因,。

這些結(jié)果證實,，CYLD在肝臟作為一種重要肝細(xì)胞穩(wěn)態(tài)調(diào)節(jié)子，通過預(yù)防TAK1和JNK不受控的激活,，保護(hù)著細(xì)胞免受自發(fā)凋亡之害,。(生物谷bioon.com)

doi:10.1016/j.cell.2011.10.017
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Inactivation of the Deubiquitinase CYLD in Hepatocytes Causes Apoptosis, Inflammation, Fibrosis, and Cancer

Kostas Nikolaou, Ageliki Tsagaratou, Christina Eftychi, George Kollias, George Mosialos, Iannis Talianidis

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.