TAK1 Suppresses a NEMO-Dependent but NF-κB-Independent Pathway to Liver Cancer

被引：220

作者：

Bettermann, Kira ^{[1
]}

Vucur, Mihael ^{[1
]}

Haybaeck, Johannes ^{[4
]}

Koppe, Christiane ^{[1
]}

Janssen, Joern ^{[1
]}

Heymann, Felix ^{[1
]}

Weber, Achim ^{[4
]}

Weiskirchen, Ralf ^{[2
]}

Liedtke, Christian ^{[1
]}

Gassler, Nikolaus ^{[3
]}

Mueller, Michael ^{[5
]}

de Vos, Rita ^{[6
]}

Wolf, Monika Julia ^{[4
]}

Boege, Yannick ^{[4
]}

Seleznik, Gitta Maria ^{[4
]}

Zeller, Nicolas ^{[7
]}

Erny, Daniel ^{[7
]}

Fuchs, Thomas ^{[8
]}

Zoller, Stefan ^{[9
]}

Cairo, Stefano ^{[10
,11
]}

Buendia, Marie-Annick ^{[10
,11
]}

Prinz, Marco ^{[7
]}

Akira, Shizuo ^{[12
]}

Tacke, Frank ^{[1
]}

Heikenwalder, Mathias ^{[4
]}

Trautwein, Christian ^{[1
]}

Luedde, Tom ^{[1
]}

机构：

[1] Univ Hosp RWTH Aachen, Dept Internal Med 3, D-52074 Aachen, Germany

[2] Univ Hosp RWTH Aachen, Inst Clin Chem & Pathobiochem, D-52074 Aachen, Germany

[3] Univ Hosp RWTH Aachen, Inst Pathol, D-52074 Aachen, Germany

[4] Univ Zurich Hosp, Inst Neuropathol & Clin Pathol, Dept Pathol, CH-8091 Zurich, Switzerland

[5] Wageningen Univ, Dept Nutr Metab & Genom, NL-6709 PA Wageningen, Netherlands

[6] Univ Leuven, Univ Hosp, Dept Pathol, B-3000 Louvain, Belgium

[7] Univ Freiburg, Dept Neuropathol, D-79106 Freiburg, Germany

[8] ETH, Dept Comp Sci, CH-8092 Zurich, Switzerland

[9] Bioinformat Funct Genom Ctr Zurich, CH-8057 Zurich, Switzerland

[10] Inst Pasteur, Oncogenesis & Mol Virol Unit, F-75724 Paris, France

[11] INSERM, U579, F-75724 Paris, France

[12] Osaka Univ, WPI Immunol Frontier Res Ctr, Host Def Lab, J-5650871 Osaka, Japan

来源：

CANCER CELL | 2010年 / 17卷 / 05期

基金：

欧洲研究理事会;

关键词：

HEPATOCELLULAR-CARCINOMA; CHEMICAL HEPATOCARCINOGENESIS; PROTEIN-KINASES; ACTIVATION; MICE; INFLAMMATION; INJURY; CELL; JNK; HEPATOCYTES;

D O I：

10.1016/j.ccr.2010.03.021

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 [肿瘤学];

摘要：

The MAP3-kinase TGF-beta-activated kinase 1 (TAK1) critically modulates innate and adaptive immune responses and connects cytokine stimulation with activation of inflammatory signaling pathways. Here, we report that conditional ablation of TAK1 in liver parenchymal cells (hepatocytes and cholangiocytes) causes hepatocyte dysplasia and early-onset hepatocarcinogenesis, coinciding with biliary ductopenia and cholestasis. TAK1-mediated cancer suppression is exerted through activating NF-kappa B in response to tumor necrosis factor (TNF) and through preventing Caspase-3-dependent hepatocyte and cholangiocyte apoptosis. Moreover, TAK1 suppresses a procarcinogenic and pronecrotic pathway, which depends on NF-kappa B-independent functions of the I kappa B-kinase (IKK)-subunit NF-kappa B essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-kappa B-independent function of NEMO in parenchymal liver cells.

引用

页码：481 / 496

页数：16

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