How transient becomes stable: An epigenetic switch linking liver inflammation and tumorigenesis

Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4 alpha initiates hepatocellular transformation through a microRNA-inflammatory feedback loop circuit consisting of miR-124, IL6R, STAT3, miR-24, and miR-629. Moreover, we show that, once this circuit is activated, it maintains suppression of HNF4 alpha and sustains oncogenesis. Systemic administration of miR-124, which modulates inflammatory signaling, prevents and suppresses hepatocellular carcinogenesis by inducing tumor-specific apoptosis without toxic side effects. As we also show that this HNF4a circuit is perturbed in human hepatocellular carcinomas, our data raise the possibility that manipulation of this microRNA feedback-inflammatory loop has therapeutic potential for treating liver cancer. (c) 2012 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.