TY - JOUR
T1 - An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis
AU - Hatziapostolou, Maria
AU - Polytarchou, Christos
AU - Aggelidou, Eleni
AU - Drakaki, Alexandra
AU - Poultsides, George A.
AU - Jaeger, Savina A.
AU - Ogata, Hisanobu
AU - Karin, Michael
AU - Struhl, Kevin
AU - Hadzopoulou-Cladaras, Margarita
AU - Iliopoulos, Dimitrios
N1 - Funding Information:
This work was supported by DFCI CIA start-up funds to D.I. and research grants to M.K. from the National Institutes of Health (RO1-CA118165 and P42-ES0100337). We would like to thank the Nikon Imaging Center at Harvard Medical School for their help with light microscopy. Also, we would like to thank Hye-Jung Kim for her assistance with the flow cytometry analysis and Virgilio Garcia for his technical support.
PY - 2011/12/9
Y1 - 2011/12/9
N2 - 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.
AB - 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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U2 - 10.1016/j.cell.2011.10.043
DO - 10.1016/j.cell.2011.10.043
M3 - Article
C2 - 22153071
AN - SCOPUS:83255162659
SN - 0092-8674
VL - 147
SP - 1233
EP - 1247
JO - Cell
JF - Cell
IS - 6
ER -
