Reciprocal activation between ATPase inhibitory factor 1 and NF-κB drives hepatocellular carcinoma angiogenesis and metastasis

Authors

  • Ruipeng Song,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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    • These authors contributed equally to this work.

  • Huiwen Song,

    1. Department of Cardiovascular Medicine and Central Laboratory, Affiliated Baoan Hospital of Southern Medical University, ShenZhen, China
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    • These authors contributed equally to this work.

  • Yingjian Liang,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Dalong Yin,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Heng Zhang,

    1. Department of Medicine, Medical College, China Three Gorges University, Yichang, Hubei, China
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  • Tongsen Zheng,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Jiabei Wang,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Zhaoyang Lu,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Xuan Song,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Tiemin Pei,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Youyou Qin,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Yuejin Li,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Changming Xie,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Boshi Sun,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Huawen Shi,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Shuai Li,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Xianzhi Meng,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Guangchao Yang,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Shangha Pan,

    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Jiyuan Zhu,

    1. Department of Pathology, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Shuyi Qi,

    1. Department of Gerontology, First Affiliated Hospital of Harbin Medical University, Harbin, China
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  • Hongchi Jiang,

    Corresponding author
    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
    • Address reprint requests to: Lianxin Liu, M.D., Ph.D., Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, #23 Youzheng Street, Harbin, 150001, Heilongjiang Province, China. E-mail: liulx@ems.hrbmu.edu.cn; fax: +86-451-53670428; or Zhiyong Zhang, M.D., Ph.D., Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, State University of New Jersey, 125 Paterson St., New Brunswick, NJ, 08901. E-mail: zhangz2@rwjms.rutgers.edu or zhiyongzhng3@gmail.com; fax: 732-235-6853; or Hongchi Jiang, M.D., Ph.D., Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, #23 Youzheng Street, Harbin, 150001, Heilongjiang Province, China. E-mail: jianghongchi01@163.com; Fax: +86-451-53643628.

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  • Zhiyong Zhang,

    Corresponding author
    1. Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, State University of New Jersey, New Brunswick, NJ, USA
    • Address reprint requests to: Lianxin Liu, M.D., Ph.D., Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, #23 Youzheng Street, Harbin, 150001, Heilongjiang Province, China. E-mail: liulx@ems.hrbmu.edu.cn; fax: +86-451-53670428; or Zhiyong Zhang, M.D., Ph.D., Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, State University of New Jersey, 125 Paterson St., New Brunswick, NJ, 08901. E-mail: zhangz2@rwjms.rutgers.edu or zhiyongzhng3@gmail.com; fax: 732-235-6853; or Hongchi Jiang, M.D., Ph.D., Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, #23 Youzheng Street, Harbin, 150001, Heilongjiang Province, China. E-mail: jianghongchi01@163.com; Fax: +86-451-53643628.

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  • Lianxin Liu

    Corresponding author
    1. Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, Harbin, China
    2. Department of Pharmacology (the State-Province Key Laboratories of Biomedicine-Pharmaceutics of China, Key Laboratory of Cardiovascular Research, Ministry of Education), Harbin Medical University, Harbin, China
    • Address reprint requests to: Lianxin Liu, M.D., Ph.D., Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, #23 Youzheng Street, Harbin, 150001, Heilongjiang Province, China. E-mail: liulx@ems.hrbmu.edu.cn; fax: +86-451-53670428; or Zhiyong Zhang, M.D., Ph.D., Department of Surgery, Robert-Wood-Johnson Medical School University Hospital, Rutgers University, State University of New Jersey, 125 Paterson St., New Brunswick, NJ, 08901. E-mail: zhangz2@rwjms.rutgers.edu or zhiyongzhng3@gmail.com; fax: 732-235-6853; or Hongchi Jiang, M.D., Ph.D., Key Laboratory of Hepatosplenic Surgery, Ministry of Education, Department of General Surgery, First Affiliated Hospital of Harbin Medical University, #23 Youzheng Street, Harbin, 150001, Heilongjiang Province, China. E-mail: jianghongchi01@163.com; Fax: +86-451-53643628.

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  • Potential conflict of interest: Nothing to report.

  • Supported by the China National Natural Science Foundation (No. 81272705), Program for Innovative Research Team by Chinese Ministry of Education (IRT1122), Program for Innovative Research Team (in Science and Technology) in Higher Educational Institutions of Heilongjiang Province (2009td06), Heilongjiang Province Science Fund for Outstanding Youths (JC200616), Foundation of Harbin Science and Technology Bureau for Creative Young Talents (2010RFQXS069), and Foundation of Health Department of Heilongjiang Province (Grant No. 2009-043). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the article.

Abstract

Hepatocellular carcinoma (HCC) is a highly vascularized tumor with frequent extrahepatic metastasis. Active angiogenesis and metastasis are responsible for rapid recurrence and poor survival of HCC. However, the mechanisms that contribute to tumor metastasis remain unclear. Here we evaluate the effects of ATPase inhibitory factor 1 (IF1), an inhibitor of the mitochondrial H(+)-adenosine triphosphate (ATP) synthase, on HCC angiogenesis and metastasis. We found that increased expression of IF1 in human HCC predicts poor survival and disease recurrence after surgery. Patients with HCC who have large tumors, with vascular invasion and metastasis, expressed high levels of IF1. Invasive tumors overexpressing IF1 were featured by active epithelial-mesenchymal transition (EMT) and increased angiogenesis, whereas silencing IF1 expression attenuated EMT and invasion of HCC cells. Mechanistically, IF1 promoted Snai1 and vascular endothelial growth factor (VEGF) expression by way of activating nuclear factor kappa B (NF-κB) signaling, which depended on the binding of tumor necrosis factor (TNF) receptor-associated factor 1 (TRAF1) to NF-κB-inducing kinase (NIK) and the disruption of NIK association with the TRAF2-cIAP2 complex. Suppression of the NF-κB pathway interfered with IF1-mediated EMT and invasion. Chromatin immunoprecipitation assay showed that NF-κB can bind to the Snai1 promoter and trigger its transcription. IF1 was directly transcribed by NF-κB, thus forming a positive feedback signaling loop. There was a significant correlation between IF1 expression and pp65 levels in a cohort of HCC biopsies, and the combination of these two parameters was a more powerful predictor of poor prognosis. Conclusion: IF1 promotes HCC angiogenesis and metastasis by up-regulation of Snai1 and VEGF transcription, thereby providing new insight into HCC progression and IF1 function. (Hepatology 2014;60:1659–1673)

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