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

Abstract

Purpose 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.

Dicer Suppresses Hepatocellular Carcinoma via Interleukin-8 Pathway

“…We have proven that Dicer inhibited HCC via downregulation of VEGF. 17 Then, we suspected that Dicer might modify HCC outcome via IL-8-VEGF axis, but VEGF expression did not change upon IL-8 or reparixin incubation in HCC cells (data not shown). This has proved that a positive feedback loop exists between EMT and IL-8 and that IL-8 promotes the occurrence of EMT, whereas EMT induces the production of IL-8 in colon cancer correspondingly.…”

“…SMMC-7721 cell transfected with green fluorescent protein (GFP)-tagged Dicer-overexpressed lentivirus (pCMV-Dicer) or negative control lentivirus (pCMV-NC) 17 was used for functional assay. The successful transfection of Dicer was confirmed by western blot analysis as described previously.…”

“…The successful transfection of Dicer was confirmed by western blot analysis as described previously. 17 …”

“… 16 We also found that Dicer enhanced the bevacizumab-related inhibition of HCC by blocking vascular endothelial growth factor (VEGF) pathway; however, the underlying mechanism has not been clarified. 17 …”

Dicer-mediated miR-200b expression contributes to cell migratory/invasive abilities and cancer stem cells properties of breast cancer cells

“…Impaired Dicer expression reduced the cisplatin sensitivity, cell proliferation and cell migration of ovarian cancer cells [ 37 ]. Moreover, the overexpression of Dicer decreased the cell proliferation, migration and invasion of hepatocellular carcinoma (HCC) cells through the vascular endothelial growth factor signaling pathway [ 38 ]. On the contrary, Dicer knockdown increased drug sensitivity in gemcitabine-resistant pancreatic cancer cells [ 23 ].…”