Department of Cancer Immunology and AIDS, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA.
Cell. 2011 Dec 9;147(6):1233-47. doi: 10.1016/j.cell.2011.10.043.
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.
肝细胞核因子 4α（HNF4α）对于肝脏发育和肝细胞功能至关重要。在这里，我们表明，HNF4α 的短暂抑制通过由 miR-124、IL6R、STAT3、miR-24 和 miR-629 组成的 microRNA-炎症反馈回路引发肝转化。此外，我们表明，一旦该回路被激活，它就会抑制 HNF4α 的表达并维持肿瘤发生。系统给予 miR-124（可调节炎症信号）可通过诱导肿瘤特异性细胞凋亡而无毒性副作用来预防和抑制肝细胞癌发生，从而发挥作用。正如我们还表明的那样，这种 HNF4α 回路在人类肝细胞癌中受到干扰，我们的数据提出了这样一种可能性，即操纵这种 microRNA 反馈炎症回路具有治疗肝癌的潜力。
