Downregulation of UHRF1 increases tumor malignancy by activating the CXCR4/AKT-JNK/IL-6/Snail signaling axis in hepatocellular carcinoma cells

摘要: Results UHRF1 deficiency promotes mesenchymal transformation via activating EMT. To validate our previous report25, we investigated whether UHRF1 deficiency is associated with the acquisition of mesenchymal characteristics in hepatocellular carcinoma cells. In this regard, we performed western blot analysis to compare the basal levels of UHRF1 and the mesenchymal marker vimentin in HepG2, Hep3B and Huh7 cells with that in normal human fetal hepatocytes (HFHs). Although the basal level of UHRF1 in these cancer cells was higher than that in HFHs, it was greatly reduced in Huh7 cells compared with the other cancer cells (Fig. 1a). However, the basal level of vimentin was highly increased in HFHs and Huh7 compared with that in HepG2 and Hep3B cells, which have relatively higher levels of UHRF1. The ability of HFHs and Huh7 cells to migrate and invade was also substantially greater than that of HepG2 and Hep3B cells, indicating that the downregulation of UHRF1 may be related to an increase in cell migratory/invasive ability and processes that are involved in EMT (Fig. 1a and b). In addition, HFHs have features similar to hepatic progenitor cells, which possess self-renewal capacity and migratory potential26. Thus, compared with these cancer cells, the relative increase in the migratory and invasive abilities of HFHs is thought to be due to these reported characteristics. To examine whether UHRF1 downregulation has a positive influence on EMT, we introduced shRNAs targeting UHRF1 (shUHRF1# 1 or shUHRF# 2) into HepG2 cells, which expresses high levels of UHRF1, and generated stable UHRF1-deficient HepG2 cells …