Dicer Enhances Bevacizumab-Related Inhibition of Hepatocellular Carcinoma via Blocking the Vascular Endothelial Growth Factor Pathway

Abstract

Cuiju Wang,1 Yalei Lv,2 Ziyue Sha,3 Jingjing Zhang,3 Jianhua Wu,4 Yixin Qi,5 Zhanjun Guo3 1Department of Gynaecology Ultrasound, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 2Department of Medical Oncology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 3Department of Immunology and Rheumatology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 4Animal Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of China; 5Breast Center, The Fourth Hospital of Hebei Medical University, Shijiazhuang, People’s Republic of ChinaCorrespondence: Yixin Qi; Zhanjun Guo Email [email protected]; [email protected]: Vascular endothelial growth factor (VEGF) family members contribute greatly to the development and angiogenesis of hypervascular hepatocellular carcinoma (HCC). We have previously shown that Dicer inhibited HCC growth. In this study, we aimed to determine the relationship between Dicer and VEGF in HCC.Methods: Gain-of-function studies were performed to determine the effect of different treatments on the proliferation, migration, and invasion of HCC cells. Expression of VEGF-A in xenograft tumor tissues was analysed using Western blotting, and that of CD31 using immunohistochemical analysis.Results: We found that Dicer inhibited proliferation, migration and invasion of HCC cells by suppressing VEGF-A expression. Interestingly, VEGF-A165, which is the most prominent VEGF-A isoform, counteracted Dicer-induced inhibition of HCC cells. In addition, a monoclonal anti-VEGF antibody (bevacizumab) enhanced Dicer-induced inhibition of HCC in vitro and in vivo. Further, immunohistochemical analysis of CD31 indicated bevacizumab and Dicer synergized to reduce tumor microvessel density.Conclusion: Our data demonstrated that Dicer enhanced bevacizumab-related inhibition of HCC cell via the VEGF pathway; therefore, Dicer in coordination with bevacizumab may provide another potential approach for HCC therapy.Keywords: hepatocellular carcinoma, vascular endothelial growth factor, Dicer, bevacizumab, microvessel density

Keywords

• hepatocellular carcinoma
• vascular endothelial growth factor
• dicer
• bevacizumab
• microvessel density