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

SummaryThe MAP3-kinase TGF-β-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-κB 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-κB-independent functions of the IκB-kinase (IKK)-subunit NF-κB essential modulator (NEMO). Therefore, TAK1 serves as a gatekeeper for a protumorigenic, NF-κB-independent function of NEMO in parenchymal liver cells.

► Deletion of TAK1 in parenchymal liver cells causes spontaneous development of hepatocellular carcinoma
► TAK1 prevents hepatocyte apoptosis by mediating TNF-dependent NF-κB activation
► NEMO acts as a tumor promoter in livers with defective TAK1
► NF-κB and IKK subunits can have distinct functions in hepatocarcinogenesis