Research led by Prof. Meital Gal-Tanaami of Bar-Ilan University and supported by the Israel Science Foundation examines how a virus that remains in the cytoplasm manages to change genetic control in the nucleus, and attempts to map points of intervention to reduce cancer risk even years after the virus has been eliminated.
Even in an era when almost every carrier of the hepatitis C virus can be cured with effective drugs, a troubling medical puzzle remains: Some patients develop liver cancer even years after the virus has disappeared from the body. Prof. Meital Gal-Tanaami, associate dean for academic research at the Azrieli Faculty of Medicine at Bar-Ilan University in the Galilee, head of the Molecular Virology Laboratory, and president of the Israeli Society for Microbiology, says that her lab has found a mechanism that may explain at least part of the phenomenon: a persistent epigenetic change in liver cells – a “stamp” that remains even after treatment. “We found that the virus changes the epigenetics in the cells, and these changes can remain as a stamp even after the virus is no longer in the cells.” Gal-Tanaami says that the stamp may maintain activation of pathways that promote the cancerous process even after the infection has ended.
What is the question? What is epigenetics?
There is no vaccine, there is a cure – but the risk is not zero.
Hepatitis C is an RNA virus that infects the liver and can, over time, cause chronic inflammation, fibrosis, cirrhosis, and liver cancer. According to her, about 20% of those infected manage to clear it naturally, but in about 80% the infection becomes chronic. Currently, there is no vaccine against the virus, but in the last decade, advanced antiviral drugs have appeared that cure about 99% of patients. Despite this, “people are cured of the virus, but after a year, two, three, four years – they still come back with liver cancer,” she says. According to the data she presents, during an active chronic infection, the risk of liver cancer may reach about 4% per year; after cure, it drops to about 1% per year – a significant decrease, but not zero.
How does a virus that remains in the cytoplasm affect the DNA in the nucleus?
Epigenetics is a layer of control that regulates which genes are turned on and which are turned off, without changing the DNA sequence. You can think of it as a “signaling system” that directs the reading of genes. The lab’s finding is that hepatitis C creates epigenetic changes in the liver that lead to changes in gene expression, including genes and pathways related to cancer, and that these changes may persist even after the virus is cleared. This raises a fundamental biological question: Hepatitis C is a virus whose life cycle occurs in the cytoplasm and does not enter the nucleus. “So how does it make changes in the nucleus, in our DNA? What mechanisms does it activate so that downstream they will cause epigenetic changes?” she explains. “It doesn’t enter the nucleus, and yet we see a change in the nucleus.”
Multi-omics and a mouse model to try to “reverse”
The research, supported by the National Science Foundation (ISF), aims to map the chain that connects infection to the cancer marker and predisposition. To this end, a “multi-omics” approach is planned that unites data on epigenetics, gene expression, proteome and signaling pathways, and sometimes also metabolomics. The goal is to integrate the layers of information to identify key points that the virus “turns on,” and then to examine whether they can be targeted with drug therapy. The practical goal is to try to perform reversion: to return the liver cells, as much as possible, to the “pre-infection” state, thus reducing the risk of cancer even after treatment.
Epigenetics is a layer of control that regulates which genes are turned on and which remain off, without changing the DNA sequence. You can think of it as a “signal system” that directs the reading of genes.
Another challenge is to separate the contribution of the virus itself from the contribution of inflammation and scarring in the liver. Because hepatitis C naturally infects only humans and chimpanzees, and it is difficult to obtain liver samples at any stage, the lab uses a mouse model with a similar virus that infects the liver, causes inflammation and fibrosis, and can even lead to liver cancer. This allows us to compare acute infection that resolves on its own with chronic infection that can be induced in an experiment, and to examine when the imprint is formed, whether it appears even after a short exposure time, and whether the type of drug has an effect on the degree to which the imprint remains.
long covid and- HPV
Gal-Tanaami adds that the idea of a “stamp” that remains after recovery may also be relevant to other viruses, such as Long Covid, and even to situations in which cancer develops without the virus itself being detectable, as has been suggested in some HPV cases. In her view, the scientific message is clear: not to be satisfied with the news that the virus is gone, but to strive for a cure that also erases the traces it left. Therefore, even after recovery, she emphasizes the importance of medical monitoring and imaging for patients at risk over time.
More of the topic in Hayadan:
One response
If the study identifies the exact pathway by which the virus causes cancer, will it be possible to use it to neutralize possible cancer in other risk groups?