Biological breakthrough that could offer new hope in the fight against liver cancer

Jul 21 2005

Scientists at The University of Nottingham have announced an important biological breakthrough that could offer new hope in the fight against liver cancer.

Professor John Mayer and Dr Simon Dawson, in collaboration with colleagues at Japan's Kyoto University, have discovered the function of a new liver oncoprotein - or cancer causing protein - which could be the first step to finding effective new treatments for the deadly illness.

The research, published in the journal Cancer Cell, centres on the most common malignant liver cancers, hepatocellular carcinomas, which arise from the liver cells themselves. Primary liver cancer is relatively rare in the UK and other countries in the Western world, but is very common in Africa and Asia - it is strongly associated with hepatitis virus infection and with a natural toxin called aflatoxin which is present in mouldy peanuts, soybeans, groundnut, corn and rice. There is currently no cure for primary liver cancer and survival rates are low.

The latest work by the Nottingham team has shown that a natural process in the liver, which would normally lead to cells dying before they can become cancerous, is being disrupted by the oncoprotein gankyrin.

The research stems from an international collaboration that began five years ago - the Nottingham team joined forces with Professor Jun Fujita and colleagues at Kyoto University after learning that both had simultaneously discovered the same new gene, which they intuitively believed played a significant role in liver cancer. Together they set about identifying the function of the new gene.

The team has found that in most cases of liver-derived cancers the gene is overexpressed. It is this gene that produces gankyrin, which effectively stimulates the destruction of another vital protein in the liver called p53, which is essential in protecting the liver from cancer.

The process is part of the ubiquitin proteasome system (UPS) - the body's natural method of breaking down proteins discovered by Aaron Ciechanover and Avram Hershko of the Israel Institute of Technology and Irwin Rose of the University of California, for which they were awarded the 2004 Nobel Prize for Chemistry.

The protein p53, sometimes called the 'guardian of the genome', is charged with the task of regulating cell division in the liver - it decides which cells should continue dividing and replicating their DNA and which should die. If a cell is infected with a virus, p53 sends out a signal to the cell, triggering a process called apoptosis - in which the cell effectively commits suicide.

In primary liver cancer, the team of scientists have discovered that this process is disrupted. Instead, the gankyrin binds to an enzyme called mdm2, which gives the p53 protein a molecular label which marks it for death. It is sent to the cell's waste disposer, the proteasome, where it is broken down and destroyed. Damaged cells can then continue dividing and growing into a tumour.

The next step is to learn more about how and why this takes place, in the hope that eventually new therapies could be developed that will disrupt this biological process and halt the growth of tumours.