Loss of hepatic NF-kappa B activity enhances chemical hepatocarcinogenesis through sustained c-Jun N-terminal kinase 1 activation.
A major link between inflammation and cancer is provided by NF-kappaB transcription factors. Ikkbeta(Deltahep) mice, which specifically lack IkappaB kinase beta (IKKbeta), an activator of NF-kappaB, in hepatocytes, are unable to activate NF-kappaB in response to proinflammatory stimuli, such as TNF-alpha. Surprisingly, Ikkbeta(Deltahep) mice are hypersusceptible to diethylnitrosamine (DEN)-induced hepatocarcinogenesis. Because defective NF-kappaB activation promotes sustained c-Jun N-terminal kinase (JNK) activation in cells exposed to TNF-alpha, whose expression is induced by DEN, and JNK activity is required for normal hepatocyte proliferation, we examined whether increased susceptibility to DEN-induced hepatocarcinogenesis in Ikkbeta(Deltahep) mice requires JNK activation. Hepatocytes express both JNK1 and JNK2, but previous studies indicate that JNK1 is more important for hepatocyte proliferation. We therefore investigated this hypothesis using mice homozygous for a JNK1 deficiency either in wild-type or Ikkbeta(Deltahep) backgrounds. In both cases, mice lacking JNK1 were much less susceptible to DEN-induced hepatocarcinogenesis. This impaired tumorigenesis correlated with decreased expression of cyclin D and vascular endothelial growth factor, diminished cell proliferation, and reduced tumor neovascularization. Whereas hepatocyte-specific deletion of IKKbeta augmented DEN-induced hepatocyte death and cytokine-driven compensatory proliferation, disruption of JNK1 abrogated this response. In addition to underscoring the importance of JNK1-mediated hepatocyte death and compensatory proliferation, these results strongly suggest that the control of tissue renewal through the IKK and JNK pathways plays a key role in liver carcinogenesis.
Sakurai
Toshiharu
T
Laboratory of Gene Regulation and Signal Transduction, School of Medicine, University of California at San Diego, 9500 Gilman Drive MC 0723, La Jolla, CA 92093-0723, USA.
Maeda
Shin
S
Chang
Lufen
L
Karin
Michael
M
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D004052:Diethylnitrosamine / Q000633:toxicity; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D051550:I-kappa B Kinase / Q000172:deficiency / Q000235:genetics; D008113:Liver Neoplasms / Q000139:chemically induced* / Q000201:enzymology* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D048055:Mitogen-Activated Protein Kinase 8 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*
D000477:Alkylating Agents; D016328:NF-kappa B; D004052:Diethylnitrosamine; D051550:I-kappa B Kinase; C496562:Ikbkb protein, mouse; D048055:Mitogen-Activated Protein Kinase 8