Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation

Cancer Cell. 2010 Mar 16;17(3):286-97. doi: 10.1016/j.ccr.2009.12.048.


The NF-kappaB activating kinase IKKbeta suppresses early chemically induced liver tumorigenesis by inhibiting hepatocyte death and compensatory proliferation. To study IKKbeta'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 IKKbeta long after initiation accelerated HCC development and enhanced proliferation of tumor initiating cells. These effects of IKKbeta/NF-kappaB 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-kappaB and STAT3, which is also evident in human HCC, is a critical regulator of liver cancer development and progression.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Gene Deletion
  • Hepatocytes / metabolism*
  • Hepatocytes / transplantation
  • Humans
  • I-kappa B Kinase / genetics
  • I-kappa B Kinase / metabolism
  • I-kappa B Kinase / physiology*
  • Liver Neoplasms / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • NF-kappa B / metabolism
  • NF-kappa B / physiology*
  • Oxidative Stress*
  • STAT3 Transcription Factor / metabolism*
  • Transcriptional Activation


  • NF-kappa B
  • STAT3 Transcription Factor
  • I-kappa B Kinase