Hepatocyte IKK β / NF-κ B inhibits tumor promotion and progression by preventing oxidative stress driven STAT 3 activation

The NF-κB activating kinase IKKβ suppresses early chemically-induced liver tumorigenesis by inhibiting hepatocyte death and compensatory proliferation. To study IKKβ’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 a long latency. Deletion of IKKβ long after initiation accelerated HCC development and enhanced proliferation of tumor initiating cells. These effects of IKKβ/NF-κB were cell autonomous and correlated with increased accumulation of reactive oxygen species (ROS) that led to JNK and STAT3 activation. Hepatocyte-specific STAT3 ablation prevented HCC development. The negative crosstalk between NF-κB and STAT3, which is also evident in human HCC, is a critical regulator of liver cancer development and progression.

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