Hepatocyte nuclear factor-4α reverses malignancy of hepatocellular carcinoma through regulating miR-134 in the DLK1-DIO3 region

Authors

  • Chuan Yin,

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

  • Pei-Qin Wang,

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

  • Wen-Ping Xu,

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

  • Yuan Yang,

    1. Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
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    • These authors contributed equally to this work.

  • Qing Zhang,

    1. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
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  • Bei-Fang Ning,

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

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

    1. Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China
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  • Wei-Fen Xie,

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

    Corresponding author
    1. Department of Pharmacy, Changzheng Hospital, Second Military Medical University, Shanghai, China
    • Address reprint requests to: Xin Zhang, Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China. E-mail: zhang68@hotmail.com Fax: +86–21–8188–9624; or Wan-Sheng Chen, Department of Pharmacy, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China. E-mail: chenws126@126.com

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  • Xin Zhang

    Corresponding author
    1. Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, Shanghai, China
    • Address reprint requests to: Xin Zhang, Department of Gastroenterology, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China. E-mail: zhang68@hotmail.com Fax: +86–21–8188–9624; or Wan-Sheng Chen, Department of Pharmacy, Changzheng Hospital, Second Military Medical University, 415 Fengyang Road, Shanghai 200003, China. E-mail: chenws126@126.com

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  • Potential conflict of interest: Nothing to report.

  • Supported by the National Natural Science Foundation of China (81071842, 81270033; Key Program 81230011; Creative Research Groups 30921006), the China National Key Projects for Infectious Disease (2013ZX10002007-007), the Shanghai Science and Technology Committee for Key Projects (11JC1416200 and 10431903600), and the Rising-Star Program (11QA1408800).

Abstract

Hepatocyte nuclear factor-4α (HNF4α) is a dominant transcriptional regulator of hepatocyte differentiation and hepatocellular carcinogenesis. There is striking suppression of hepatocellular carcinoma (HCC) by HNF4α, although the mechanisms by which HNF4α reverses HCC malignancy are largely unknown. Herein, we demonstrate that HNF4α administration to HCC cells resulted in elevated levels of 28 mature microRNAs (miRNAs) from the miR-379-656 cluster, which is located in the delta-like 1 homolog (DLK1) -iodothyronine deiodinase 3 (DIO3) locus on human chromosome 14q32. Consistent with the reduction of HNF4α, these miRNAs were down-regulated in human HCC tissue. HNF4α regulated the transcription of the miR-379-656 cluster by directly binding to its response element in the DLK1-DIO3 region. Interestingly, several miRNAs in this cluster inhibited proliferation and metastasis of HCC cells in vitro. As a representative miRNA in this cluster, miR-134 exerted a dramatically suppressive effect on HCC malignancy by down-regulating the oncoprotein, KRAS. Moreover, miR-134 markedly diminished HCC tumorigenicity and displayed a significant antitumor effect in vivo. In addition, inhibition of endogenous miR-134 partially reversed the suppressive effects of HNF4α on KRAS expression and HCC malignancy. Furthermore, a positive correlation between HNF4α and miR-134 levels was observed during hepatocarcinogenesis in rats, and decreases in miR-134 levels were significantly associated with the aggressive behavior of human HCCs. Conclusion: Our data highlight the importance of the miR-379-656 cluster in the inhibitory effect of HNF4α on HCC, and suggest that regulation of the HNF4α-miRNA cascade may have beneficial effects in the treatment of HCC. (Hepatology 2013; 58:1964–1976)

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