ZEB1 mediates doxorubicin (Dox) resistance and mesenchymal characteristics of hepatocarcinoma cells.

The acquired chemoresistance during long term chemotherapy is one of the most important factors to limit the application of Doxorubicin (Dox) on clinical treatment of hepatocellular carcinoma (HCC) patients. Our present study found that Dox resistant HCC (HCC/Dox) cells had greater capability of in vitro migration and invasion compared to their parental cells. HCC/Dox cells exhibited mesenchymal characteristics, which was evidenced by the up regulation of fibronectin, vimentin while down regulation of E-Cadherin. Zeb1, one powerful epithelial mesenchymal transition related transcription factor (EMT-TF), was markedly upregulated in HCC/Dox cells. Targeted inhibition of Zeb1 via siRNA can suppress the cell migration and re-sensitized cells to Dox treatment. The upregulation of Zeb1 in HCC/Dox cells was due to the increasing protein and mRNA stability of Zeb1. In HCC/Dox cells, the down regulation of SIAH1 mediated the upregulation of protein stability of Zeb1, while decreased levels of miR-3129-5p was responsible for the increasing mRNA stability of Zeb1. Collectively, our data suggested that SIAH1 and miR-3129-5p induced upregulation of Zeb1 mediated the Dox resistance of HCC cells. Targeted inhibition of Zeb1 might be helpful to overcome of Dox resistance of HCC.