Department of Internal Medicine III, University Hospital RWTH Aachen, D-52074 Aachen, Germany.
Cancer Cell. 2010 May 18;17(5):481-96. doi: 10.1016/j.ccr.2010.03.021.
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-kappaB 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-kappaB-independent functions of the I kappaB-kinase (IKK)-subunit NF-kappaB essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-kappaB-independent function of NEMO in parenchymal liver cells.
MAP3-kinase 转化生长因子-β激活激酶 1（TAK1）可显著调节固有和适应性免疫反应，并将细胞因子刺激与炎症信号通路的激活联系起来。在这里，我们报告称，在肝实质细胞（肝细胞和胆管细胞）中条件性敲除 TAK1 会导致肝细胞增生和早期肝癌发生，同时伴有胆管减少和胆汁淤积。TAK1 通过响应肿瘤坏死因子 (TNF) 激活 NF-κB 并通过防止 Caspase-3 依赖性肝细胞和胆管细胞凋亡来发挥其抑制肿瘤的作用。此外，TAK1 还抑制了一种促癌和促坏死的途径，该途径依赖于 NF-κB 非依赖性的 IκB 激酶 (IKK)-亚基 NF-κB 必需调节剂 (NEMO) 的功能。因此，TAK1 是 NEMO 在实质肝细胞中具有促肿瘤发生、NF-κB 非依赖性功能的守门员。
