An HNF4alpha-miRNA Inflammatory Feedback Circuit Regulates Hepatocellular Oncogenesis
Cette étude met en évidence le rôle du facteur nucléaire HNF4 alpha dans un mécanisme reliant inflammation et cancérogenèse hépatocellulaire
Hepatocyte nuclear factor 4alpha (HNF4alpha) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4alpha 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 HNF4alpha 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 HNF4alpha 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. º HNF4alpha transient inhibition induces hepatocellular transformation º The HNF4alpha feedback loop circuit links inflammation to liver cancer º MiR-124 regulates IL6-STAT3-signaling pathway º Systemic delivery of miR-124 inhibits HCC development Transient inhibition of a key liver transcription factor promotes cellular transformation and liver cancer by stabilizing a microRNA-mediated inflammatory circuit.