Hepatocyte nuclear factor 4a (HNF4a) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4a 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 HNF4a 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.
View details for DOI 10.1016/j.cell.2011.10.043
View details for Web of Science ID 000298148100014
View details for PubMedID 22153071
View details for PubMedCentralID PMC3251960