ABSTRACT
Objective:To investigate the role of NRF2 pathway in the drug resistance to sorafenib in hepatocellular carcinoma (HCC).Methods:Two sorafenib-resistant cells HepG2-SR and Huh7-SR were established by incubating human HCC HepG2 and Huh7 cells at a increasing concentration of sorafenib,and verify resistant cell properties by detecting the cell apoptosis.The levels of NRF2 were detected by Western blot and Real-time PCR.SiRNA was used to silence NRF2,then the cell apoptosis were detected by flow cytometry to explore the effect of reversing the drug resistance and synergy in combination with sorafenib.Results:Sorafenib induced pro-apoptosis effect was significantly in Huh7 and HepG2 cells than the corresponding Huh7-SR and HepG2-SR cells.The NRF2 expression levels were significantly higher in sorafenib-resistant cells and the parental cells treated with sorafenib than the corresponding untreated parental cells,while the NFR2 mRNA expression levels were no significant.When in combination with sorafenib,NRF2 siRNA showed the synergistic effect in inducing cell apoptosis in sorafenib-resistant cells and parental cells.Conclusion:NRF2,activated by post-transcriptional level after sorafenib exposure,is responsible for the drug resistance to sorafenib in HCC.Inhibiting NRF2 could reverse the drug resistance to sorafenib in HCC.