Effects of sorafenib and regorafenib on the expression of hypoxia-inducible factors in hepatocellular carcinoma-transplanted nude mice

Abstract

Abstract Objective The objective of this study was to investigate the inhibitory effects of sorafenib and regorafenib on the growth of hepatocellular carcinoma (HCC) using a subcutaneous transplantation tumor model in nude mice and exploring the effects of sorafenib and regorafenib on the expression of hypoxia-inducible factor (HIF)-1α, HIF-2α, and HIF-1β in HCC tissues collected from HCC-transplanted nude mice. Methods HepG2 cells were inoculated intradermally into nude mice. The mice were randomly assigned to either sorafenib treatment (100 mg/kg), regorafenib treatment (20 mg/kg), or solvent control group (dimethylsulfoxide) (n = 8 per group) and received once-daily treatment for 14 days. The tumor volumes were recorded every 3 days after the initiation of treatment. The expression levels of HIF-1α, HIF-1β, HIF-2α, and SART1 in the HCC tissues were examined via quantitative real-time PCR (qRT-PCR) analysis and Western blotting. Results The tumors in the sorafenib and regorafenib treatment groups grew slower and smaller than did the tumors in the solvent control group. qPCR analysis and western blotting demonstrated that the mRNA and protein expressions of HIF-1α and HIF-1β were down-regulated. The expression of HIF-2α and SART1 was up-regulated in the sorafenib treatment group (P < 0.05); meanwhile, the expression of HIF-1α and HIF-1β was up-regulated, and that of HIF-2α and SART1 was down-regulated in the regorafenib treatment group (P < 0.05). Conclusion The expression of hypoxia-associated factor is up-regulated by sorafenib and down-regulated by regorafenib, which may induce the different effects of sorafenib on the expression of HIFs.