Dual role of caspase-8 extends understanding of liver cancer
Liver cancer predominantly occurs in people who have chronic liver diseases, such as viral hepatitis, fatty liver disease, and cholestatic disease. All chronic liver diseases show persistent hepatocyte (liver cell) damage. Hepatocyte apoptosis, a hallmark of chronic liver diseases, is thought to play opposing roles. On the one hand, apoptosis helps eliminate damaged hepatocytes, maintaining liver homeostasis and preventing mutation accumulation. On the other hand, increased levels of apoptosis can be harmful.
A study, conducted by researchers from the University of Zurich and many other research organizations, provides new insight into the development of liver cancer. Hepatocyte apoptosis determines and predicts hepatocellular carcinoma (HCC) development, and the enzyme caspase-8 plays a dual role in this mechanism, the researchers report Monday in Cancer Cell.
HCC is the most prevalent type of liver cancer, comprising about 75% of all primary liver cancers. HCC happens when hepatocytes become malignant. According to estimates, HCC kills 662,000 people worldwide annually. Most of the deaths are in Africa and Asia. The prognosis of HCC is quite poor.
Achim Weber, corresponding author of the study and professor of molecular pathology at the University Hospital Zurich, focuses on liver carcinogenesis. In the present study, Weber and co-workers explored the interactions between caspase-8-dependent hepatocyte apoptosis, genetic instability, liver regeneration, and liver carcinogenesis.
Caspase-8 is a caspase protein encoded by the CASP8 gene. Caspase-8 is involved in apoptosis, a process of programmed cell death.
Working with tissue samples from patients with chronic liver disease, Weber's team found that chronic liver diseases display elevated levels of hepatocyte apoptosis, which correlate with increased hepatocyte proliferation and liver regeneration. Additionally, chronic liver diseases display high levels of DNA damage and genetic instability. Measurement of serum levels of ALT and AST revealed that chronic liver disease patients who developed HCC had much higher ALT and AST levels before their cancer diagnosis.
The team also carried out experiments in mouse models and cell lines. They found that caspase-8 not only executes hepatocyte apoptosis but also functions in DNA damage response. Along with other molecules, caspase-8 helps detect and repair DNA damage in hepatocytes. This function of caspase-8 may prevent against liver carcinogenesis.
To better understand the connection between caspase-8 and HCC, the researchers analyzed public databases of HCC patients and found that low caspase-8 expression is linked with a better overall survival.
These data suggest that caspase-8 may have a dual role in liver cancer. Caspase-8 is involved in hepatocyte apoptosis and sensing DNA damage. Besides, the study provides insight into how increased hepatocyte apoptosis contributes to subsequent liver cancer development.
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