Research details the role of c-Fos in liver cancer

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Research details the role of c-Fos in liver cancer

Postby whbio » Apr 11 2017 3:50 pm

Hepatocellular carcinoma (HCC) is the dominant form of primary liver cancer, and it originates from hepatocytes, the major cell type of the liver. Most patients with HCC get it in the setting of chronic liver damage and inflammation. It has been shown that human HCCs express the protein c-Fos, which is a component of the protein complex AP-1. AP-1 is a transcription factor that regulates gene expression in response to various stimuli, and it has been linked with liver diseases such as fatty liver disease. Better understanding of c-Fos’ role in HCC development may lead to new treatments.

Now researchers from the Spanish National Cancer Research Centre, Medical University of Vienna, and Aarhus University reveal that c-Fos is necessary for the development of HCC. The team conducted experiments in genetically modified mouse models, and found that hepatocyte-specific deletion of c-Fos protected mice from developing HCC when the mice were exposed to diethylnitrosamine (a chemical carcinogen). By contrast, liver-specific c-Fos expression resulted in premalignant hepatocyte transformation and enhanced diethylnitrosamine-carcinogenesis.

Mice that expressed c-Fos in their liver showed cell damage, immune cell infiltration, and altered hepatocyte morphology. Moreover, the researchers detected gene signatures of aggressive HCCs and many other markers for liver dysfunction and premalignant transformation of hepatocytes. Importantly, when the researchers turn off c-Fos, these changes disappeared.

Further investigation revealed that c-Fos reduces expression and activity of LXRα, a nuclear receptor protein crucial for controlling cholesterol homeostasis, leading to hepatic accumulation of cholesterol and toxic cholesterol derivatives that raise the risk of cancer. This might explain why c-Fos expression in hepatocytes induces changes associated with HCC. Treatment with a class of cholesterol-lowering medications, statins, significantly ameliorated the harmful consequences of c-Fos expression. The findings were published in The Journal of Experimental Medicine. (Cusabio offers c-Fos, LXRα, and other proteins.
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