An HNF4α-miRNA Inflammatory Feedback Circuit Regulates Hepatocellular Oncogenesis

Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Cell (Impact Factor: 32.24). 12/2011; 147(6):1233-47. DOI: 10.1016/j.cell.2011.10.043
Source: PubMed


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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Available from: Maria Hatziapostolou, Apr 01, 2014
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    • "A single positive feedback loop can amplify a signal, create a bistable switch, or enhance the robustness to noise (Brandman and Meyer, 2008; Wang et al., 2010; Kim and Cho, 2012). Additionally, constitutive activation of a positive feedback loop can contribute to the development of tumors by triggering the sustained activation of proliferative signaling (Iliopoulos et al., 2009; Hatziapostolou et al., 2011; Opitz et al., 2011). To explore how PI3K/AKT-mediated positive feedback regulation shapes Wnt signaling and how RORa-mediated negative feedback regulation prevents undesirable activation of Wnt signaling , we measured the induction of Cyclin D1 in response to Wnt stimulation when the following three key components were varied: AKT in the positive feedback loop, RORa in the negative feedback loop, and the DC (destruction complex), which is involved in the APC mutation. "
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