Hepatocyte Nuclear Factor 4α-Nuclear Factor-κB Feedback Circuit Modulates Liver Cancer Progression

Hepatocyte nuclear factor 4 alpha (HNF4 alpha) is a liver enriched transcription factor and is indispensable for liver development. However, the role of HNF4 alpha in hepatocellular carcinoma (HCC) progression remains to be elucidated. We report that reduced HNF4 alpha expression correlated well with the aggressive clinicopathological characteristics of HCC and predicted poor prognosis of patients. HNF4 alpha levels were even lower in metastatic HCCs, and ectopic HNF4 alpha expression suppressed the metastasis of hepatoma cells both in vitro and in vivo. Forced HNF4 alpha expression attenuated the expression and nuclear translocation of RelA (p65) and impaired NF-kappa B activation through an IKKindependent mechanism. Blockage of RelA robustly attenuated the suppressive effect of HNF4 alpha on hepatoma cell metastasis. MicroRNA (miR)-7 and miR-124 were transcriptionally up-regulated by HNF4 alpha, which repressed RelA expression by way of interaction with RelA-3' untranslated region (UTR). In addition, nuclear factor kappa B (NF-kappa B) up-regulated the expression of miR-21 in hepatoma cells, resulting in decreased HNF4 alpha levels through down-regulating HNF4 alpha-3'UTR activity. Conclusions: Collectively, an HNF4 alpha-NF-kappa B feedback circuit including miR-124, miR-7, and miR-21 was identified in HCC, and the combination of HNF4 alpha and NF-kappa B 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.