EIF3C-enhanced exosome secretion promotes angiogenesis and tumorigenesis of human hepatocellular carcinoma
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Hsin-Yi Lee1,2, Chi-Kuan Chen3,4, Chun-Ming Ho2,5,6, Szu-Shuo Lee2,7, Chieh-Yu Chang2,8, Kuan-Ju Chen2,9 and Yuh-Shan Jou1,2,6,7,8,9
1Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan
2Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
3Department of laboratory medicine, MacKay Memorial Hospital, Taipei, Taiwan
4School of medicine, MacKay Medical College, Taipei, Taiwan
5Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan
6Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan
7Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan
8Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan
9Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan
Yuh-Shan Jou, email: [email protected]
Keywords: Hepatocellular carcinoma; EIF3C; exosome; angiogenesis; S100A11
Received: October 11, 2017 Accepted: January 03, 2018 Published: January 11, 2018
Targeting tumor angiogenesis is a common strategy against human hepatocellular carcinoma (HCC). However, identification of molecular targets as biomarker for elevating therapeutic efficacy is critical to prolong HCC patient survival. Here, we showed that EIF3C (eukaryotic translation initiation factor 3 subunit C) is upregulated during HCC tumor progression and associated with poor patient survival. Expression of EIF3C did not alter proliferation and expression of other tumor progressive genes such as HIF1A, TGFβ1 and VEGF, but reduced cell migration in HCC cells. Nevertheless, expression of EIF3C in HCC cells significantly increase secretion of extracellular exosomes confirmed by increased exosomes labelling by PKH26 fluorescent dye, vesicles in exosome size detected by electronic microscopy and nanoparticle tracking analysis, and expression of divergent exosome markers. The EIF3C-increased exosomes were oncogenic to potentiate tumor angiogenesis via tube formation of HUVEC cells and growth of vessels by plugs assays on nude mice. Subcutaneous inoculation of EIF3C-exosomes mixed with Huh7 HCC cells not only promoted growth of vessels but also increased expression of EIF3C in tumors. Conversely, treatment of exosome inhibitor GW4869 reversed aforementioned oncogenic assays. We identified EIF3C activated expression of S100A11 involved in EIF3C-exosome increased tube formation in angiogenesis. Simultaneous high expression of EIF3C and S100A11 in human HCC tumors for RNA level in TCGA and protein level by IHC are associated with poor survival of HCC patients. Collectively, our results demonstrated that EIF3C overexpression is a potential target of angiogenesis for treatment with exosome inhibitor or S100A11 reduction to suppress HCC angiogenesis and tumorigenesis.
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