Researchers find molecule that helps keep liver cancer-free
A molecular pathway which helps to protect the liver from hepatitis and cancer has been identified by a European team of researchers. Their work, which was partly funded by the EU's Sixth Framework Programme (FP6) under the 'Life Sciences, Genomics and Biotechnology for Health' priority, is published in the latest edition of the journal Cancer Cell. Liver cancer is one of the deadliest cancers; most victims die within a year of diagnosis. According to recent figures from the International Agency for Research on Cancer, in 2006 there were 48,000 cases of liver cancer in the EU, and 42,600 deaths. However, little is known about the molecular mechanisms behind this disease. Now researchers have uncovered how the transcription factor NF-kB helps to protect the liver from hepatitis and liver cancer. Normally, NF-kB acts as a survival signal, helping cells to escape programmed death. Using genetic techniques, the scientists created a mouse whose liver did not produce a protein called NEMO, which activates the NF-kB molecule. 'The mice first developed a condition similar to fatty liver disease and hepatitis in humans and later on liver tumours,' said Professor Manolis Pasparakis of the University of Cologne, one of the authors of the research. 'This suggests that NEMO and NF-kB have an important role in protecting the liver from cancer and could act as yet unknown tumour suppressors.' The researchers believe that the death of the cells lacking NEMO triggered a compensatory response in the liver. 'The liver has unique ways to regenerate after injury; upon cell death it tells other cells to proliferate and to make up for the loss,' explained Tom Luedde, a member of Professor Pasparakis' laboratory. 'This situation is very stressful and energy consuming for the liver, so that errors and mutations are likely to happen which then lead to tumours.' The fact that NF-kB activation is apparently essential for a healthy liver has important implications for researchers working on diseases where NF-kB activation is the problem. For example, NF-kB is activated in many cancer cells, where it is thought to provide a survival signal that helps the malignant cells avoid cell death. It has also been implicated in inflammatory diseases, and last year Professor Pasparakis' team found that the NF-kB pathway was responsible for aggravating the symptoms of multiple sclerosis. In all these cases, blocking the NF-kB pathway has been seen as a promising approach for new therapies. 'The results reported in this study raise important considerations for pharmacological therapies targeting the IKK [IkappaB kinase] complex in human patients, which has been suggested as a powerful approach to treat inflammatory and other disorders,' the researchers write. 'Our experiments show that complete inhibition of IKK activity in hepatocytes might be detrimental and might result in liver disease and even liver cancer upon long term treatment.' 'NF-kB signalling is incredibly complex, and a lot of research will be necessary to understand it to the point when we can safely manipulate it with drugs,' commented Professor Pasparakis.