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Alcohol and hepatitis C are a dangerous cocktail, Keck researchers find

The study, led by Keigo Machida, appeared in the February issue of the Proceedings of the National Academy of Sciences

A new study led by researchers at the Keck School of Medicine found that drinking alcohol greatly increases the chances that a patient infected by the hepatitis C virus (HCV) will develop a common type of liver cancer.

The study appeared earlier this month in the Proceedings of the National Academy of Sciences.

The research clarifies the complex molecular events that link alcoholism and HCV to increased risk of hepatocellular carcinoma (HCC), the fifth most common cancer worldwide, said Keigo Machida, Ph.D., assistant professor of molecular microbiology and immunology at the Keck School.

There is ample evidence that chronic liver damage caused by viral infection, alcohol, metabolic syndrome or these factors in combination can increase the risk for HCC, Machida said. However, the molecular mechanism for the synergy among alcohol, HCV and liver cancer has remained unclear.

“Understanding the molecular link holds great potential for future treatment of this particular form of liver cancer,” Machida said. “The signaling mechanism gives researchers a new drug therapy target for treating HCC.”

Machida and his colleagues focused their research on a viral protein, NS5A, which they had found in earlier experiments stimulated high expression of a receptor for bacterial endotoxins, known as Toll-like receptor 4 (TLR4). Alcohol intake increases the risk of leaking bacterial toxin from the gut, which the researchers believe causes over-activation of endotoxin receptor signaling if patients are also infected by HCV.

This excess antibacterial reaction then results in an increased risk of tumor growth should the body’s natural anti-tumor response weaken as a result of the infection, Machida explained.

Researchers conducted a series of experiments with mice and also examined liver biopsy samples from human patients infected with HCV, and found high levels of the protein NS5A and TLR4. In the subset of patients who were also alcoholics, the researchers saw signs of increased antibacterial response. The research also identified a specific molecule called Nanog, which acts as a stem cell marker in tumor development when activated by TLR4.

“There were several major findings that resulted from this study,” Machida said. “We established a mouse model which will enable us to better understand alcohol and hepatitis C virus infection and we found the signaling that causes tumor development in mice through the receptor TLR4.”

“More research is needed, but if we are able to target and suppress these molecules identified in the study, we may be able to stop the cancer’s lifeline.”

The study was supported by National Institute on Alcohol Abuse and Alcoholism/National Institutes of Health-funded Southern California Research Center for Alcoholic Liver and Pancreatic Diseases and Cirrhosis (P50AA11199) headquartered at the Keck School of Medicine.

Alcohol and hepatitis C are a dangerous cocktail, Keck researchers find

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