Open AccessAn HNF4α-miRNA Inflammatory Feedback Circuit Regulates Hepatocellular Oncogenesis
Author(s) -
Maria Hatziapostolou,
Christos Polytarchou,
Eleni Aggelidou,
Alexandra Drakaki,
George A. Poultsides,
Savina Jaeger,
Hisanobu Ogata,
Michael Karin,
Kevin Struhl,
Margarita HadzopoulouCladaras,
Dimitrios Iliopoulos
Publication year - 2011
Publication title -
cell
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 26.304
H-Index - 776
eISSN - 1097-4172
pISSN - 0092-8674
DOI - 10.1016/j.cell.2011.10.043
Subject(s) - hepatocyte nuclear factor 4 , biology , carcinogenesis , cancer research , microrna , hepatocyte , hepatocyte nuclear factors , liver cancer , inflammation , stat3 , hepatocellular carcinoma , signal transduction , microbiology and biotechnology , cancer , immunology , gene expression , nuclear receptor , gene , transcription factor , genetics , in vitro
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.
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