An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis.
An HNF4α-miRNA inflammatory feedback circuit regulates hepatocellular oncogenesis.
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DOI：
10.1016/j.cell.2011.10.043
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发表时间：
2011-12-09
期刊：
影响因子：
64.5
通讯作者：
Iliopoulos D
中科院分区：
文献类型：
--
作者：
Hatziapostolou M;Polytarchou C;Aggelidou E;Drakaki A;Poultsides GA;Jaeger SA;Ogata H;Karin M;Struhl K;Hadzopoulou-Cladaras M;Iliopoulos D
肝细胞核因子4α（HNF 4 α）是肝脏发育和肝细胞功能所必需的。在这里，我们发现HNF 4 α的瞬时抑制通过由miR-124，IL-6 R，STAT 3，miR-24和miR-629组成的microRNA-炎症反馈回路启动肝细胞转化。此外，我们表明，一旦这个电路被激活，它保持抑制HNF 4a和维持肿瘤发生。全身性施用调节炎症信号传导的miR-124通过诱导肿瘤特异性细胞凋亡来预防和抑制肝细胞癌发生，而没有毒副作用。由于我们还表明这种HNF 4 α回路在人类肝细胞癌中受到干扰，我们的数据提高了操纵这种microRNA反馈-炎症回路对治疗肝癌具有治疗潜力的可能性。
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 HNF4a 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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