Critical role and regulation of transcription factor foxm1 in human gastric cancer angiogenesis and progression

Abstract

The mammalian forkhead box (Fox) transcription factor FoxMlb is implicated in tumorigenesis. However, the presence of expression and role of FoxMlb in gastric cancer remain unknown. Therefore, we investigated FoxMlb expression in 86 cases of primary gastric cancer and 57 normal gastric tissue specimens. We further investigated the underlying mechanisms of altered FoxMlb expression in and the effect of this altered expression on gastric cancer growth and metastasis using in vitro and animal models of gastric cancer. We found weak expression of FoxMlb protein in the mucous neck region of gastric mucosa, whereas we observed strong staining for FoxMlb in tumor cell nuclei in various gastric tumors and lymph node metastases. A Cox proportional hazards model revealed that FoxMlb expression was an independent prognostic factor in multivariate analysis (P<0.001). Experimentally, overexpression of FoxMlb by gene transfer significantly promoted the growth and metastasis of gastric cancer cells in orthotopic mouse models, whereas knockdown of FoxMlb expression by small interfering RNA did the opposite. Promotion of gastric tumorigenesis by FoxMlb directly and significantly correlated with transactivation of vascular endothelial growth factor expression and elevation of angiogenesis. Given the importance of FoxMlb to regulation of the expression of genes key to cancer biology overall, dysregulated expression and activation of FoxMlb may play important roles in gastric cancer development and progression. copy; 2009 American Association for Cancer Research.