Hepatocyte nuclear factor 4α-nuclear factor-κB feedback circuit modulates liver cancer progression.

Abstract

UNLABELLED:

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.

CONCLUSIONS:

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.

• Authors: Bei-Fang Ning, Jin Ding, Jiao Liu, Chuan Yin, Wen-Ping Xu, Wen-Ming Cong, Qing Zhang, Fei Chen, Tao Han, Xing Deng, Pei-Qin Wang, Cai-Feng Jiang, Jun-Ping Zhang, Xin Zhang, Hong-Yang Wang, Wei-Fen Xie
• Journal: Hepatology (Baltimore, Md.) (Hepatology) Vol. 60 Issue 5 Pg. 1607-19 (Nov 2014) ISSN: 1527-3350 [Electronic] United States
• PMID: 24752868 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2014 by the American Association for the Study of Liver Diseases.

Chemical References

• Hepatocyte Nuclear Factor 4
• MicroRNAs
• NF-kappa B
• RELA protein, human
• Transcription Factor RelA

Topics

• Adult
• Aged
• Aged, 80 and over
• Animals
• Carcinoma, Hepatocellular (metabolism, mortality)
• Cells, Cultured
• China (epidemiology)
• Disease Progression
• Epithelial-Mesenchymal Transition
• Feedback, Physiological
• Female
• Hepatocyte Nuclear Factor 4 (metabolism)
• Humans
• Liver Neoplasms (metabolism, mortality)
• Male
• MicroRNAs (metabolism)
• Middle Aged
• NF-kappa B (metabolism)
• Rats, Wistar
• Transcription Factor RelA (metabolism)
• Young Adult