Hepatitis Virus Knocks Out Tumor Suppressor

The hepatitis virus can knock out one copy of a tumor-suppressor gene and make seemingly healthy liver cells much more prone to uncontrolled, cancerous growth, researchers report in today's issue of the Proceedings of the National Academy of Sciences. The finding indicates a way to detect liver cancer in its early stages.

Mutations in a gene called M6P/IGR2R have previously been implicated in liver cancer. This gene, suspected to be a tumor suppressor, codes for a protein that regulates cell proliferation by both activating a growth inhibitor and degrading a growth factor. The absence of this gene is a "double whammy" for controlling cell growth, says Randy Jirtle of the Duke University Medical Center, like a car that has lost its brakes at the same time its gas pedal jammed. Jirtle decided to find out whether it was a tumor suppressor by seeing if it was inactivated in the hepatitis patients, because they are a such high risk of liver cancer.

To test their idea, the researchers looked at tissue sections from the livers of 27 patients with a history of hepatitis infection who had had their livers removed. None of these livers had developed the large 12-centimeter tumors characteristic of late-stage cancer, but all had 1-centimeter lesions. The cells in the small tumors lacked both copies of the M6P/IGR2R gene, but more surprisingly, a large volume of seemingly normal tissue around the lesions had only one functional copy of the gene. Moreover, all this defective tissue was clonal in origin, indicating that it had grown from one imperfect cell and spread as the liver tried to regenerate cells.

Whether the hepatitis virus directly mutates or deletes the gene or whether the effect is more indirect is still unknown. But medical benefits of the finding could be immediate. "This sheds light on the mechanisms of liver cancer," says Sanford Markowitz, a cancer geneticist at Case Western Reserve University in Cleveland. "It has potential for early detection of people at risk."

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