MicroRNA-26a suppresses angiogenesis in human hepatocellular carcinoma by targeting hepatocyte growth factor-cMet pathway

Authors

  • Xin Yang,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China. Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Xiao-Fei Zhang,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China. Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Xu Lu,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China. Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Hu-Liang Jia,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China. Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Lei Liang,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China. Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Qiong-Zhu Dong,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China. Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Qing-Hai Ye,

    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China. Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
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  • Lun-Xiu Qin

    Corresponding author
    1. Liver Cancer Institute & Zhongshan Hospital, Institutes of Biomedical Science, Fudan University, Shanghai, China. Key Laboratory of Carcinogenesis & Cancer Invasion, Ministry of Education, China
    • Address reprint requests to: Lun-Xiu Qin, M.D., Ph.D., Liver Cancer Institute and Zhongshan Hospital, Fudan University, 180 Feng Lin Road, Shanghai 200032, China. E-mail: qin.lunxiu@zs-hospital.sh.cn; fax: +86-21-5423 7960.

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  • Potential conflict of interest: Nothing to report.

  • Supported by China National Key Projects for Infectious Disease (2008ZX10002-021, 2012ZX10002-012), the National Key Basic Research Program of China (2013CB910500; 2009CB521701), Program for Changjiang Scholars and Innovative Research Team (the Ministry of Education of China; IRT1118), Program of Shanghai Chief Scientist (08XD14008), China National Natural Science Foundation (81120108016; 30600589), Program for Outstanding Medical Academic Leader (LJ10010).

Abstract

MicroRNA (miR)-26a can suppress tumor growth and metastasis of hepatocellular carcinoma (HCC). Since angiogenesis is important for tumor growth and metastasis, we investigated the possible roles of miR-26a in tumor angiogenesis. Down-regulation of miR-26a was found to correlate with an increased angiogenic potential of HCC. Through gain- and loss-of-function studies, miR-26a was demonstrated to significantly inhibit vascular endothelial growth factor A (VEGFA) expression in HCC cells and then suppress the promoting effects of HCC cells on in vitro proliferation, migration, and capillary tube formation of endothelial cells, as well as in vivo tumor angiogenesis of HCC. Hepatocyte growth factor (HGF) was identified as a target of miR-26a. HGF simulation antagonized the effects induced by miR-26a up-regulation. In contrast, silencing HGF induced similar effects to miR-26a. We further found that miR-26a exerted its antiangiogenesis function, at least in part, by inhibiting HGF-hepatocyte growth factor receptor (cMet) and its downstream signaling pathway, in turn, suppressing VEGFA production in HCC cells and impairing VEGFR2-signaling in endothelial cells. HCC patients who had high miR-26a, low HGF, low VEGFA, or low microvessel density (MVD) in tumor tissues had a better prognosis with longer overall survival (OS) and time to recurrence (TTR). In multivariate analysis, miR-26a, or in combination with HGF, was demonstrated to be an independent prognostic indicator for OS and TTR of HCC patients. Conclusion: miR-26a could suppress tumor angiogenesis of HCC through HGF-cMet signaling, and it is a new hopeful therapeutic target and prognostic marker for HCC. (Hepatology 2014;59:1874–1885)

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