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

Authors

  • Bei-Fang Ning,

    1. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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    • These authors contributed equally to this work.

  • Jin Ding,

    1. International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
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    • These authors contributed equally to this work.

  • Jiao Liu,

    1. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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    • These authors contributed equally to this work.

  • Chuan Yin,

    1. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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  • Wen-Ping Xu,

    1. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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  • Wen-Ming Cong,

    1. Department of Pathology, Eastern Hepatobiliary Surgery Hospital, Second Military Medical University, Shanghai, China
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  • Qing Zhang,

    1. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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  • Fei Chen,

    1. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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  • Tao Han,

    1. International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
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  • Xing Deng,

    1. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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  • Pei-Qin Wang,

    1. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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  • Cai-Feng Jiang,

    1. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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  • Jun-Ping Zhang,

    1. Department of Pharmacology, School of Pharmacy, Second Military Medical University, Shanghai, China
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  • Xin Zhang,

    1. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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  • Hong-Yang Wang,

    Corresponding author
    1. International Cooperation Laboratory on Signal Transduction of Eastern Hepatobiliary Surgery Institute, Second Military Medical University, Shanghai, China
    • Address reprint requests to: Dr. Wei-Fen Xie, Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, 200003 Shanghai, China. E-mail: weifenxie@medmail.com.cn; fax: 86-21-63520020 or Dr. Hong-yang Wang, International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, 200438 Shanghai, China. E-mail: hywangk@vip.sina.com

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  • Wei-Fen Xie

    Corresponding author
    1. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
    • Address reprint requests to: Dr. Wei-Fen Xie, Department of Gastroenterology, Shanghai Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, 200003 Shanghai, China. E-mail: weifenxie@medmail.com.cn; fax: 86-21-63520020 or Dr. Hong-yang Wang, International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, Second Military Medical University, 225 Changhai Road, 200438 Shanghai, China. E-mail: hywangk@vip.sina.com

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  • Potential conflict of interest: Nothing to report.

  • See Editorial on Page 1466

  • Supported by grant Key Program (81230011), Creative Research Groups (81221061), Distinguished Young Scholars (30825020), Excellent Young Scholars (81222034) and Young Scholar (81201938) from the National Natural Science Foundation of China, and grant from Shanghai Science and Technology Committee (12ZR1439300).

Abstract

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. (Hepatology 2014;60:1607-1619)

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