Critical Role and Regulation of Transcription Factor FoxM1 in Human Gastric Cancer Angiogenesis and Progression

Abstract

The mammalian Forkhead Box (Fox) transcription factor FoxM1b is implicated in tumorigenesis. However, the presence of expression and role of FoxM1b in gastric cancer remain unknown. Therefore, we investigated FoxM1b expression in 86 cases of primary gastric cancer and 57 normal gastric tissue specimens. We further investigated the underlying mechanisms of altered FoxM1b expression in and the impact of this altered expression on gastric cancer growth and metastasis using in vitro and animal models of gastric cancer. We found weak expression of FoxM1b protein in the mucous neck region of gastric mucosa, whereas we observed strong staining for FoxM1b in tumor-cell nuclei in various gastric tumors and lymph node metastases. A Cox proportional hazards model revealed that FoxM1b expression was an independent prognostic factor in multivariate analysis (P < 0.001). Experimentally, overexpression of FoxM1b by gene transfer significantly promoted the growth and metastasis of gastric cancer cells in orthotopic mouse models, whereas knockdown of FoxM1b expression by small interfering RNA did the opposite. Promotion of gastric tumorigenesis by FoxM1b directly and significantly correlated with transactivation of vascular endothelial growth factor (VEGF) expression and elevation of angiogenesis. Given the importance of FoxM1b to regulation of the expression of genes key to cancer biology overall, dysregulated expression and activation of FoxM1b may play important roles in gastric cancer development and progression.

Expression Signature Defined byFOXM1–CCNB1Activation Predicts Disease Recurrence in Non–Muscle-Invasive Bladder Cancer

“…S4). FOXM1 is frequently associated with metastasis and patient survival in many types of cancers (28,29); it was also reported that FOXM1 activity was significantly increased in bladder cancers relative to normal bladder tissues and might have a prognostic value at the individual level (30). CCNB1, a downstream effector of FOXM1, is upregulated and is known to be a prognostic biomarker in many cancers (25)(26)(27).…”

Expression and significance of FOXM1 in human cervical cancer: A tissue micro-array study

“…Furthermore, a striking reduction in the number and size of lung tumors was found following the deletion of FOXM1 from lung epithelial cells prior to tumor initiation in transgenic mice, which resulted primarily from a signi cant decrease in TOPO-2α, a direct target of FOXM1. FOXM1B, the predominant FOXM1 isoform, could directly promote gastric tumorigenesis by regulating the expression of genes key to cancer biology overall [21]. Disruption of the FOXM1-cyclin B1 regulatory loop is one of the mechanisms of the negative regulation of hepatocarcinogenesis [22].…”

Knockdown of FoxM1 by siRNA interference decreases cell proliferation, induces cell cycle arrest and inhibits cell invasion in MHCC-97H cells in vitro

“…In In vivo, loss of FoxM1 is embryonic lethal due to a failure to enter mitosis [8][9][10] . Recent studies showed that FoxM1 was overexpressed in several kinds of cancer, such as lung cancer, glioblastomas and gastric cancer, and had an important role in the development and progression of those cancers [5,[11][12][13] . FoxM1 expression is tightly associated with proliferation and is extinguished in differentiated or resting cells that have exited the cell cycle.…”