Hepatocyte IKKbeta/NF-kappaB inhibits tumor promotion and progression by preventing oxidative stress-driven STAT3 activation.
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.
Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California, San Diego, La Jolla, CA 92093, USA.
Guobin
G
He
Guann-Yi
GY
Yu
Vladislav
V
Temkin
Hisanobu
H
Ogata
Christian
C
Kuntzen
Toshiharu
T
Sakurai
Wolfgang
W
Sieghart
Markus
M
Peck-Radosavljevic
Hyam L
HL
Leffert
Michael
M
Karin
D000818:Animals; D017353:Gene Deletion; D022781:Hepatocytes / Q000378:metabolism* / Q000637:transplantation; D006801:Humans; D051550:I-kappa B Kinase / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D008113:Liver Neoplasms / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016328:NF-kappa B / Q000378:metabolism / Q000502:physiology*; D018384:Oxidative Stress; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D015533:Transcriptional Activation
D016328:NF-kappa B; D050796:STAT3 Transcription Factor; D051550:I-kappa B Kinase