肝细胞核因子
异位表达
癌症研究
转录因子
小RNA
肝细胞核因子4
医学
生物
细胞培养
核受体
基因
遗传学
作者
Beifang Ning,Jin Ding,Jiao Liu,Chuan Yin,Wenrong Xu,Cong Wang,Qing Zhang,Fei Chen,Tao Han,Xiangbing Deng,Pei‐Qin Wang,Cai‐Feng Jiang,Junping Zhang,Xin Zhang,Hongyang Wang,Wei‐Fen Xie
出处
期刊:Hepatology
[Wiley]
日期:2014-06-27
卷期号:60 (5): 1607-1619
被引量:85
摘要
Hepatocyte nuclear factor 4α (HNF4α) is a liver enriched transcription factor and is indispensable for liver development. However, the role of HNF4α in hepatocellular carcinoma (HCC) progression remains to be elucidated. We report that reduced HNF4α expression correlated well with the aggressive clinicopathological characteristics of HCC and predicted poor prognosis of patients. HNF4α levels were even lower in metastatic HCCs, and ectopic HNF4α expression suppressed the metastasis of hepatoma cells both in vitro and in vivo. Forced HNF4α expression attenuated the expression and nuclear translocation of RelA (p65) and impaired NF-κB activation through an IKK-independent mechanism. Blockage of RelA robustly attenuated the suppressive effect of HNF4α on hepatoma cell metastasis. MicroRNA (miR)-7 and miR-124 were transcriptionally up-regulated by HNF4α, which repressed RelA expression by way of interaction with RelA-3' untranslated region (UTR). In addition, nuclear factor kappa B (NF-κB) up-regulated the expression of miR-21 in hepatoma cells, resulting in decreased HNF4α levels through down-regulating HNF4α-3'UTR activity.Collectively, an HNF4α-NF-κB feedback circuit including miR-124, miR-7, and miR-21 was identified in HCC, and the combination of HNF4α and NF-κB exhibited more powerful predictive efficiency of patient prognosis. These findings broaden the knowledge of hepatic inflammation and cancer initiation/progression, and also provide novel prognostic biomarkers and therapeutic targets for HCC.
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