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

Abstract

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.

TAK1 control of cell death

“…Nonetheless, these tissue injuries are associated with caspase activation and are not rescued by Ripk3 deletion, indicating that they are primarily apoptosis. 37,49,55,57,[82][83][84][85]88 We note here that the role of TAK1 in vivo may not be limited to prevention of cell death. For example, Tak1-deficient neutrophils hyperproliferate rather than dying spontaneously, leading to splenomegaly and myelomonocytic leukemia.…”

“…55,56 Hepatocyte-specific deletion of TAK1 triggers TNFa-dependent liver injury and hepatocellular carcinoma within 6 weeks of age, whereas loss of NF-kB activation by NEMO deletion causes much milder liver injury around 20 weeks of age. 57 Furthermore, it appears that NF-kB activity is not always regulated by TAK1 in some tissues in vivo. For example, Tak1 deletion in blood vessels leads to TNFa-induced endothelial cell death without altering NF-kB activity.…”

“…37 Hepatocyte-specific deletion of Tak1 also causes cell death and liver injury. 57,83 However, unlike epithelial and endothelial tissues, Tak1 deficiency in hepatocytes does not cause profound tissue damage and is not associated with immediate animal mortality. Instead, Tak1-deficient hepatocyte death induces inflammation and promotes compensatory proliferation, which eventually leads to hepatocellular carcinoma within 6 weeks.…”

“…Instead, Tak1-deficient hepatocyte death induces inflammation and promotes compensatory proliferation, which eventually leads to hepatocellular carcinoma within 6 weeks. 57,83 Hematopoietic-specific Tak1 deletion depletes hematopoietic progenitor cells, T cells and macrophages. [10][11][12]58,[84][85][86][87] Deletion of TNF receptor 1 (Tnfr1) largely rescues these injuries and animal mortalities, 37,55,57,[82][83][84][85] demonstrating that TNFa is the major killer of Tak1-deficient cells in these tissues.…”

“…Lethal E10-11 8,25,119 (Epidermis) Increased cell death-4Lethal P5-7 82 (Intestinal epithelium) Increased cell death-4Lethal P0 55 (Inducible intestinal epithelium) Ileitis and loss of paneth cells 55,65 (Endothelium/blood vessel) Increased cell death, defective vascularization-4Lethal E10-11 37 (Liver) Increased cell death-4Hepatocellular carcinoma within 6 weeks of age 57,83 (Hematopoietic system) Increased cell death-4Depletion of stem cells [84][85][86] (Myeloid) Macrophage death, splenomegaly and hyperproliferation of neutrophils 87,89 Tab1 Lethal E15-16 120 There is a well-studied inhibitory regulation from apoptosis to necroptosis (Figure 4, blue inhibition arrow). Thus, inhibition of caspase-8 activates necroptosis.…”