Mouse Liver-Cancer Model Highlights Chronic Inflammation and Fibrosis

Investigators at the University of California, San Diego (UCSD; USA) and Osaka University (Japan) have been studying the role of TGF-beta-activated kinase 1 (Tak1) in the development of liver cancer. Tak1 is a MAP3K (mitogen-activated protein kinase) family member that activates NF-kappaB and JNK.
NF-kappaB (nuclear factor kappa-light-chain-enhancer of activated B cells) is a protein complex that controls the transcription of DNA. NF-kappaB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, ultraviolet irradiation, oxidized LDL, and bacterial or viral antigens. c-Jun N-terminal kinases (JNKs) are mitogen-activated protein kinases which are responsive to stress stimuli, such as cytokines, ultraviolet irradiation, heat shock, and osmotic shock and are involved in T cell differentiation and apoptosis.

In the current study, the investigators genetically engineered a line of mice whose liver cells were Tak1-deficient. They reported in the December 18, 2009, online edition of journal Proceedings of the [U.S.] National Academy of Sciences (PNAS) that .the Tak1-deficient mice displayed spontaneous hepatocyte death, compensatory proliferation, inflammatory cell infiltration, and fibrosis at age one month. Older Tak1- deficient mice developed multiple cancer nodules characterized by increased expression of fetal liver genes including alpha-fetoprotein.

"TAK1 appears to be a master regulator of liver function," said contributing author Dr. David A. Brenner, professor of medicine at UCSD. "Understanding its role in liver disease and cancer may eventually enable us to devise new therapeutic strategies."

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University of California, San Diego
Osaka University