Title: Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation.
Authors: He, Guobin; Yu, Guann-Yi; Temkin, Vladislav; Ogata, Hisanobu; Kuntzen, Christian; Sakurai, Toshiharu; Sieghart, Wolfgang; Peck-Radosavljevic, Markus; Leffert, Hyam L; Karin, Michael
Published In Cancer Cell, (2010 Mar 16)
Abstract: 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.
PubMed ID: 20227042
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