Background and Aim: Cellular senescence is gaining importance for its role in tumor suppression and has been induced by many chemotherapeutic agents that may be negatively regulated by forkhead box M1 (FoxM1) gene expression.Previous studies revealed that hypoxia reduced cellular senescence in some cancers which might be involved hypoxiainducible factor 1 (HIF-1α).FoxM1 is predicted as a transcriptional target of MicroRNA-34a (miR-34a) that is down-regulated in hepatoma cell lines.To date, no studies exist that link a relationship between HIF-1α/miR-34a and FoxM1 in senescence of hepatocellular carcinoma (HCC) cells.Methods: Growth inhibition of oxaliplatin on HepG2, HuH-7 and Hep3B cells were assessed using a 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT)assay and colony formation.Cell cycle analysis was performed by flow cytometry and also assessed with the β-Galactosidase assay.Hepatoma cells were transfected by Lipofectamine 2000 with FoxM1 siRNA, pcDNA 3.1-FoxM1, HIF-1α siRNA, pcDNA 3.1-HIF-1α,miR-34a mimics and inhibitor.Senescence-related proteins in every groups cells were evaluated by quantitative reverse transcriptase-PCR (qRT-PCR), Western blot analysis,immuno-histochemistry and-fluorescence.Results: Hypoxia decreases stress induced senescence of HepG2, HuH-7 and Hep3B cells.Concomitantly, the mRNA and protein levels of p53 and p21 were increased, whereas the level of p16INK4a remain unchanged.Interestingly, the expression of FoxM1 increased significantly after stress-induced senescence in hypoxia condition.Furthermore,regulation of FoxM1 by RNA interference and overexpresion vector transfection markedly affect the cell cycle and senescence via regulating cycle related factors including p27,cyclin B1 and cyclin D1.Immuno histochemistry showed that FoxM1 expression is significantly correlated with with HIF-1αprotein in hepatocellular carcinoma tissues.Such correlation was due to the direct binding of HIF-1α to the HIF-1α binding sites in the FoxM1 promoter.By deletion and mutation assays, we demonstrated that the HIF1α-1 and HIF1α-3/4 binding sites on the FoxM1 promoter were essential for transcriptional activation of FoxM1 by hypoxia.Silencing of HIF-lα increases stress-induced senescence via repressing Foxml expression.Furthermore, we found that miR-34a inhibits FoxM1 expression through a miR-34a-binding site within the 3'-UTR of FoxM1.miR-34a inhibition of FoxMl leads to an increase cellular senescence in hypoxia condition.Conclusion: Our results reveal a functional link between FoxM1 with stress-induced cellular senescence.This phenomenon is regulated by HIF-1α/miR-34a, which may be used as potential target to improve the treatment of HCC.