An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis

Maria Hatziapostolou, Christos Polytarchou, Eleni Aggelidou, Alexandra Drakaki, George A. Poultsides, Savina A. Jaeger, Hisanobu Ogata, Michael Karin, Kevin Struhl, Margarita Hadzopoulou-Cladaras, Dimitrios Iliopoulos

Research output: Contribution to journalArticlepeer-review

345 Citations (Scopus)

Abstract

Hepatocyte nuclear factor 4α (HNF4α) is essential for liver development and hepatocyte function. Here, we show that transient inhibition of HNF4α 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 HNF4α 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 HNF4α 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.

Original languageEnglish
Pages (from-to)1233-1247
Number of pages15
JournalCell
Volume147
Issue number6
DOIs
Publication statusPublished - Dec 9 2011

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)

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