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.
Highlights
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death in the world with more than 788,000 death per year based on data presented in the World Health Organization (WHO)
We found that EIF3C is upregulated in HCC tumor samples in comparison with normal tissues in The Cancer Genome Atlas (TCGA) HCC dataset (Figure 1A)
To extend our understanding how aberrant translational machinery participated in tumorigenesis, we investigated the roles of upregulated-EIF3C in association with poor patient survival and served as theranostic target for improving HCC therapy
Summary
Hepatocellular carcinoma (HCC) is the third leading cause of cancer death in the world with more than 788,000 death per year based on data presented in the World Health Organization (WHO). Another multiple kinase inhibitor regorafenib showed 10~20% response rate as second-line therapy for advanced HCC was approved by FDA in 2017 [5] Both multiple kinase inhibitors showed anti-angiogenesis activity by targeting angiogenic and oncogenic receptor tyrosine kinases with modest improvement of HCC patient survival [6]. Extracellular vesicles were released as heterogeneous plasma membrane vesicles from majority of cell types into body fluids under normal or disease conditions for intercellular communication [24] Based on their size and biogenesis, extracellular vesicles in diameter could be mainly divided into exosomes (30~150 nm), microvesicles (or microparticles) (100 nm~1 μm) and apoptotic bodies (>1 μm) as cargos for transmitting proteins, lipids, coding RNAs, noncoding RNAs such as microRNAs or even DNA to target cells for inducing various signaling cascades [25]. Rather than direct stimulation of tumorigenic features such as cell proliferation and cell migration, we found an interesting mechanism that expression of EIF3C in HCC cells increase secretion of exosomes to promote angiogenesis and tumorigenesis of HCC with cross-validations of markers in human HCC tumor samples
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
