An HNF4?-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis.

ABSTRACT: Hepatocyte nuclear factor 4? (HNF4?) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4? 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? 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 HNF4? 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.

SUBMITTER: Hatziapostolou M 

PROVIDER: S-EPMC3251960 | biostudies-literature | 2011 Dec

REPOSITORIES: biostudies-literature