Metformin reverses stem cell-like HepG2 sphere formation and resistance to sorafenib by attenuating epithelial-mesenchymal transformation

Cancer stem cells (CSCs) have been reported to be associated with the recurrence and drug resistance of liver cancer. In the present study, stem cell-like HepG2 cell spheres were enriched using stem cell conditioned culture medium. As expected, stem-like HepG2 cell spheres exhibited increased resistance to sorafenib. Metformin, a common drug used to treat type 2 diabetes mellitus, reduced the diameters and numbers of stem-like HepG2 spheres, and increased their sensitivity to sorafenib. Western blotting confirmed that low doses of metformin reversed the epithelial-mesenchymal transformation (EMT) process of HepG2 spheres. These results suggested that metformin enhanced sensitivity to sorafenib, which was probably through reversal of the EMT process of sphere-forming cells and by reducing the formation of CSCs.