Hepatocyte IKKβ/NF-κB Inhibits Tumor Promotion and Progression by Preventing Oxidative Stress-Driven STAT3 Activation

The NF-kappa B activating kinase IKK beta suppresses early chemically induced liver tumorigenesis by inhibiting hepatocyte death and compensatory IKK beta's role in late tumor promotion and progression, we developed a transplant system that allows initiated mouse hepatocytes to form hepatocellular carcinomas (HCC) in host liver after along latency. Deletion of IKK beta long after initiation accelerated HCC development and enhanced proliferation of tumor initiating cells. These effects of IKK beta/NF-kappa B were cell autonomous and correlated with increased accumulation of reactive oxygen species that led to JNK and STAT3 activation. Hepatocyte-specific STAT3 ablation prevented HCC development. The negative crosstalk between NF-kappa B and STAT3, which is also evident in human HCC, is a critical regulator of liver cancer development and progression.