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Cycles of cell death, proliferation key to liver cancer

Research at the University of California, San Diego (UCSD) School of Medicine shows that liver cancer is likely caused by cycles of liver cell death and renewal.

The research, appearing online the week of June 19 in advance of publication in the journal Proceedings of the National Academy of Sciences, underscores the importance of JNK1-mediated cell death and compensatory proliferation. The findings by Michael Karin, Ph.D., professor pharmacology in UCSD¡¦s Laboratory of Gene Regulation and Signal Transduction, and colleagues strongly suggest that the control of tissue renewal through the IKK and JNK pathways plays a key role in liver cancer in mouse models.

One link between inflammation and cancer is known to involve the NF-kB pathway, which regulates gene expression. In research published in the journal Cell in 2005, Karin and his colleagues at UCSD implicated the pathway's activator, IKK , in chemically induced liver cancer. However, the surprising outcome of those studies was the finding that while NF-ƒÛB activation in hepatocytes (liver cells) prevents liver cancer, its activation in inflammatory cells, such as tissue macrophages, promotes tumor development.

In their latest work, the research team studied what precedes inflammation ¡V the injury of hepatocytes caused by toxic chemicals, which sets in motion the inflammation process.

Their research showed that the absence of IKKƒÒ in hepatocytes led to increased c-Jun N-terminal kinase (JNK) activation after exposure to a chemical carcinogen used to elicit liver cancer in mice. Importantly, deletion of the gene that codes for the major isoform of JNK in liver cells, JNK1, prevented the development of liver cancer and reversed the tumor-enhancing effect caused by ablation of IKKƒÒ.

"We found that long-term JNK activation leads to cell death; if activated briefly, it stimulates proliferation of pre-malignant and cancerous tumor cells," said Karin. Blocking JNK prevents
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Source:University of California - San Diego


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