Sorafenib inhibits proliferation and invasion of human hepatocellular carcinoma cells via up-regulation of p53 and suppressing FoxM1

Forkhead box M1 (FoxM1) is a transcription factor that plays important roles in pathogenesis and progression of human cancers, including hepatocellular carcinoma (HCC). aim of this study was to examine involvement of FoxM1 in anti-cancer action of sorafenib, a multikinase inhibitor, in human HCC cells.Methods:HCC cell lines HepG2 and HuH-7 were tested. Cell viability was examined using MTT assay and cell invasion was determined with Transwell migration assay. relevant mRNA expression was determined with RT-PCR, and proteins were detected using Western blotting and immunofluorescence assays. RNA interference was used to modify expression of p53 and FoxM1. HuH-7 cell line xenograft mice were used for in vivo study, which were treated with sorafenib (40 mg/kg, po) daily for 3 weeks.Results:Sorafenib (2-20 μmol/L) inhibited proliferation of cells in dose-and time-dependent manners with an IC 50 value of nearly 6 μmol/L at 48 h. Sorafenib (6 μmol/L) markedly suppressed cell invasion. Furthermore, sorafenib (2-6 μmol/L) dose-dependently decreased expression of FoxM1, MMP-2, and Ki-67, and up-regulated that of p53 in cells. Silencing p53 abolished decrease of FoxM1 and increase of p53 in sorafenib-treated cells. Silencing FoxM1 significantly reduced expression of MMP-2 and Ki-67, and enhanced anti-proliferation action of sorafenib in cells, whereas overexpression of FoxM1 increased expression of MMP-2 and Ki-67, and abrogated anti-proliferation action of sorafenib. In xenograft mice, sorafenib administration decreased tumor growth by 40%, and markedly increased expression of p53, and decreased expression of FoxM1, MMP-2, and Ki-67 in tumor tissues.Conclusion:Sorafenib inhibits HCC proliferation and invasion by inhibiting MMP-2 and Ki-67 expression due to up-regulation of P53 and suppressing FoxM1.