文章大意是，研究现实细胞死亡周期，炎症可能是促进癌变的重要因素。减低病源介导的肝细胞损害，比如，病毒，酒精，药物...是减低癌变的关键。 Cycles of Cell Death, Proliferation Key to Liver Cancer
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.
http://psa-rising.com/blog/index.php/2006/06/22/cycles-of-cell-death-proliferation-key-to-liver-cancer/
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发表于 2006-6-26 23:47
