BACKGROUND & AIMS: 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) metastasis remains largely unknown.
METHODS: 429 HCC tissues were involved in the correlation analysis of HNF4α levels with tumor features and patient outcomes. Effect of HNF4α on HCC metastasis was monitored through in vivo imaging system. Expression of HNF4α, RelA(p65) or microRNAs in human HCCs was determined by Real-time PCR, western blot or immunohistochemistry. Point mutation and ChIP assay were performed to detect the interaction of HNF4α with the promoter of target microRNA. 3’UTR reporter assay was conducted to determine the regulation of RelA by microRNAs.
RESULTS: 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. HNF4α suppressed HCC metastasis through inhibiting RelA expression and NFκB activity. miR-7 and miR-124, which were transcriptionally up-regulated by HNF4α, repressed RelA expression via interaction with RelA-3’UTR. Herein, HNF4α suppresses NF-κB activity and RelA expression via a miR-7 and miR-124-dependent manner. Moreover, combination of HNF4α and NF-κB exhibited more powerful predictive efficiency of patient prognosis.
CONCLUSIONS: Considering the importance of HNF4α and NF-κB in chronic liver disease, the suppression of NF-κB by HNF4α is not only essential in connecting hepatic inflammation and tumorigenesis, but also indicates novel strategy in HCC prevention and therapy.
Citation Format: Bei-Fang Ning, Jiao Liu, Wen-Ping Xu, Chuan Yin, Xin Zhang, Wei-Fen Xie. HNF4α inhibits liver cancer metastasis via suppression of NF-кB activity. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 134. doi:10.1158/1538-7445.AM2014-134