[PDF][PDF] NEMO prevents steatohepatitis and hepatocellular carcinoma by inhibiting RIPK1 kinase activity-mediated hepatocyte apoptosis

V Kondylis, A Polykratis, H Ehlken, L Ochoa-Callejero… - Cancer cell, 2015 - cell.com
V Kondylis, A Polykratis, H Ehlken, L Ochoa-Callejero, BK Straub, S Krishna-Subramanian…
Cancer cell, 2015cell.com
IκB kinase/nuclear factor κB (IKK/NF-κB) signaling exhibits important yet opposing functions
in hepatocarcinogenesis. Mice lacking NEMO in liver parenchymal cells (LPC)
spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that
NF-κB prevents liver disease and cancer. Here, we show that complete NF-κB inhibition by
combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO
deficiency, but constitutively active IKK2-mediated NF-κB activation prevented …
Summary
IκB kinase/nuclear factor κB (IKK/NF-κB) signaling exhibits important yet opposing functions in hepatocarcinogenesis. Mice lacking NEMO in liver parenchymal cells (LPC) spontaneously develop steatohepatitis and hepatocellular carcinoma (HCC) suggesting that NF-κB prevents liver disease and cancer. Here, we show that complete NF-κB inhibition by combined LPC-specific ablation of RelA, c-Rel, and RelB did not phenocopy NEMO deficiency, but constitutively active IKK2-mediated NF-κB activation prevented hepatocellular damage and HCC in NEMOLPC-KO mice. Knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) prevented hepatocyte apoptosis and HCC, while RIPK1 ablation induced TNFR1-associated death domain protein (TRADD)-dependent hepatocyte apoptosis and liver tumors in NEMOLPC-KO mice, revealing distinct kinase-dependent and scaffolding functions of RIPK1. Collectively, these results show that NEMO prevents hepatocarcinogenesis by inhibiting RIPK1 kinase activity-driven hepatocyte apoptosis through NF-κB-dependent and -independent functions.
cell.com