EIF3C-enhanced exosome secretion promotes angiogenesis and tumorigenesis of human hepatocellular carcinoma

// Hsin-Yi Lee 1, 2 , Chi-Kuan Chen 3, 4 , Chun-Ming Ho 2, 5, 6 , Szu-Shuo Lee 2, 7 , Chieh-Yu Chang 2, 8 , Kuan-Ju Chen 2, 9 and Yuh-Shan Jou 1, 2, 6, 7, 8, 9 1 Graduate Institute of Life Sciences, National Defense Medical Center, Taipei, Taiwan 2 Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan 3 Department of laboratory medicine, MacKay Memorial Hospital, Taipei, Taiwan 4 School of medicine, MacKay Medical College, Taipei, Taiwan 5 Institute of Bioinformatics and Systems Biology, National Chiao Tung University, Hsinchu, Taiwan 6 Bioinformatics Program, Taiwan International Graduate Program, Academia Sinica, Taipei, Taiwan 7 Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan 8 Taiwan International Graduate Program in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan 9 Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan Correspondence to: Yuh-Shan Jou, email: jou@ibms.sinica.edu.tw Keywords: Hepatocellular carcinoma; EIF3C; exosome; angiogenesis; S100A11 Received: October 11, 2017      Accepted: January 03, 2018      Published: January 11, 2018 ABSTRACT 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.