Liver cancer is likely caused by cycles of liver cell death and renewal, according to research at the University of California, San Diego (UCSD) School of Medicine.

The research, to appear 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.

The research team studied what precedes inflammation – liver cell damage caused by toxic chemicals, which sets in motion the inflammation process

The most common form of liver cancer, Hepatocellular carcinoma (HCC), is the third leading cause of cancer deaths worldwide. Its major risk factors are persistent infection with hepatitis B and C viruses, and exposure to toxic chemicals, including alcohol – all of which cause chronic liver injury and inflammation. Although not common in the United States., the incidence of HCC is on an upward trajectory, with little hope for treatment or cure through chemotherapy, radiation or other traditional cancer treatments.

“We now understand development of liver cancer in mice. Since inflammation drives both damage and regeneration in liver tissue, it is the repeating cycle of damage, inflammation and regeneration that leads to liver cancer,” said Karin. “However, this knowledge is not satisfactory until we find out if it applies to humans.”

One link between inflammation and cancer is known to involve the Nuclear factor-kappaB (NF-kB) pathway, which regulates gene expression. NF-kB has been termed “the central mediator of the immune response.”

“Nuclear factor-kappaB (NF-kappaB) transcription factors and the signalling pathways that activate them,” Karin writes in Nature, “are central coordinators of innate and adaptive immune responses. More recently, it has become clear that NF-kappaB signalling also has a critical role in cancer development and progression. NF-kappaB provides a mechanistic link between inflammation and cancer, and is a major factor controlling the ability of both pre-neoplastic and malignant cells to resist apoptosis-based tumour-surveillance mechanisms. NF-kappaB might also regulate tumour angiogenesis and invasiveness, and the signalling pathways that mediate its activation provide attractive targets for new chemopreventive and chemotherapeutic approaches.”

In research published in the journal Cell in 2005, Karin and his colleagues at UCSD implicated the pathway’s on/ off switch — known as Inhibitor of kappaB kinase beta (IKKbeta) — in chemically induced liver cancer.

However, the surprising outcome of those studies was the finding that while NF- kB activation in liver cells (hepatocytes) prevents liver cancer, its activation in inflammatory cells, such as tissue macrophages, promotes tumor development.

In their latest work Karin’s team showed that the absence of IKKbeta in liver cells led to increased activation of a chemical that kicks in when cells are exposed to toxins, c-Jun N-terminal kinase (JNK) . Importantly, when they deleted the gene that codes for the major isoform of JNK in liver cells, JNK1, this deletion prevented the development of liver cancer and reversed the tumor-enhancing effect caused by ablation of IKKbeta.

“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 liver injury but also inhibits liver regeneration, so the timing and context of activation are very important, he added.

“In this research, we set out to identify what causes inflammation in response to liver injury, as well as what stimulates the proliferation of surviving hepatocytes,” said Karin. “Since we previously knew that JNK activity is required for normal liver cell proliferation, we wondered if the same activity is required for production of liver cancer in carcinogen-exposed mice. The results were clear – JNK1 is critical for tumor development.”

The scientists genetically removed JNK1 to test if its increased activation, caused by the absence of IKKbeta, was responsible for accelerated tumor development. When JNK1 was removed, the number and size of cancerous liver tumors decreased, and the tumors grew more slowly. Increased JNK1 activation was found in diseased liver and tumors when compared to normal tissue.

Hepatocellular carcinoma (HCC), the most common form of liver cancer, is the third leading cause of cancer deaths worldwide. Its major risk factors are persistent infection with hepatitis B and C viruses, and exposure to toxic chemicals, including alcohol – all of which cause chronic liver injury and inflammation. Although not common in the United States., the incidence of HCC is on an upward trajectory, with little hope for treatment or cure through chemotherapy, radiation or other traditional cancer treatments.

Contributors to the paper include Toshiharu Sakurai, UCSD Laboratory of Gene Regulation and Signal Transduction and Kyoto University, Japan; Shin Maeda, UCSD and the Asahi Life Foundation, Tokyo; and Lufen Chang, UCSD and the Beckman Research Institute at City of Hope National Medical Center, Duarte, CA.

The research was supported by the National Institutes of Health and the Superfund Basic Research Program. Karin is an American Cancer Society Research Professor.

Sources for this article:
1. Cycles of Cell Death, Proliferation Key to Liver Cancer
By Debra Kain, UCSD Health Science Communcations.

2. Dr. Karin’s publications as linked above.

More Links: Michael Karin’s homepage

UCSD’s Michael Karin Follows the Cellular Pathways, ScienceWatch, 1999