PROX1 promotes hepatocellular carcinoma metastasis by way of up-regulating hypoxia-inducible factor 1α expression and protein stability

Authors

  • Yanfeng Liu,

    1. Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
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    • These authors contributed equally to this work.

  • Ju-Bo Zhang,

    1. Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (MOE), Fudan University, Shanghai, China
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    • These authors contributed equally to this work.

  • Yi Qin,

    1. Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
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    • These authors contributed equally to this work.

  • Wei Wang,

    1. Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
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  • Lili Wei,

    1. Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
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  • Yigang Teng,

    1. School of Life Science, Zhejiang Sci-Tech University, Hangzhou, China
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  • Lei Guo,

    1. Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (MOE), Fudan University, Shanghai, China
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  • Bo Zhang,

    1. Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (MOE), Fudan University, Shanghai, China
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  • Zhenhai Lin,

    1. Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (MOE), Fudan University, Shanghai, China
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  • Jing Liu,

    1. Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
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  • Zheng-Gang Ren,

    Corresponding author
    1. Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (MOE), Fudan University, Shanghai, China
    • These authors contributed equally to this work.Address reprint requests to: Dr. Y. Xie, Shanghai Medical College, Fudan University, Yixueyuan Rd. 138, Shanghai 200032, China. E-mail: yhxie@fudan.edu.cn; fax: 86-21-54237973; or

      Dr. Q. Ye or Dr. Z. Ren, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China. E-mail: ye.qinghai@zs-hospital.sh.cn or

      ren.zhenggang@zs-hospital.sh.cn.

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  • Qing-Hai Ye,

    Corresponding author
    1. Liver Cancer Institute, Zhongshan Hospital, Key Laboratory of Carcinogenesis and Cancer Invasion (MOE), Fudan University, Shanghai, China
    • These authors contributed equally to this work.Address reprint requests to: Dr. Y. Xie, Shanghai Medical College, Fudan University, Yixueyuan Rd. 138, Shanghai 200032, China. E-mail: yhxie@fudan.edu.cn; fax: 86-21-54237973; or

      Dr. Q. Ye or Dr. Z. Ren, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China. E-mail: ye.qinghai@zs-hospital.sh.cn or

      ren.zhenggang@zs-hospital.sh.cn.

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  • Youhua Xie

    Corresponding author
    1. Key Laboratory of Medical Molecular Virology (MOE & MOH), Institute of Biomedical Sciences, Shanghai Medical College, Fudan University, Shanghai, China
    • These authors contributed equally to this work.Address reprint requests to: Dr. Y. Xie, Shanghai Medical College, Fudan University, Yixueyuan Rd. 138, Shanghai 200032, China. E-mail: yhxie@fudan.edu.cn; fax: 86-21-54237973; or

      Dr. Q. Ye or Dr. Z. Ren, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Shanghai, China. E-mail: ye.qinghai@zs-hospital.sh.cn or

      ren.zhenggang@zs-hospital.sh.cn.

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  • Potential conflict of interest: Nothing to report.

  • Supported by grants from National Key Project for Infectious Diseases (2012ZX10002-006, 2012ZX10004-503, 2012ZX10002012-003), National Basic Research Program (2009CB521701, 2012CB519002), Natural Science Foundation of China (31071143, 31170148, 30872505, 81071993, 81172275), and Shanghai Municipal R&D Grant (11DZ2291900, GWDTR201216).

Abstract

Hepatocellular carcinoma (HCC) is one of the most common cancers and the third leading cause of death from cancer worldwide. HCC has a very poor prognosis because of tumor invasiveness, frequent intrahepatic spread, and extrahepatic metastasis. The molecular mechanism of HCC invasiveness and metastasis is poorly understood. The homeobox protein PROX1 is required for hepatocyte migration during mouse embryonic liver development. In this study, we show that high PROX1 protein expression in primary HCC tissues is associated with significantly worse survival and early tumor recurrence in postoperative HCC patients. Knockdown of PROX1 expression in HCC cells inhibited cell migration and invasiveness in vitro and HCC metastasis in nude mice while overexpression of PROX1 in HCC cells promoted these processes. PROX1's pro-metastasis activity is most likely attributed to its up-regulation of hypoxia-inducible factor 1α (HIF-1α) transcription and stabilization of HIF-1α protein by recruiting histone deacetylase 1 (HDAC1) to prevent the acetylation of HIF-1α, which subsequently induces an epithelial-mesenchymal transition response in HCC cells. We further demonstrated the prognostic value of using the combination of PROX1 and HDAC1 levels to predict postoperative survival and early recurrence of HCC. Conclusion: PROX1 is a critical factor that promotes HCC metastasis. (Hepatology 2013;58:692-705)

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