Deletion of Forkhead Box M1 Transcription Factor from Respiratory Epithelial Cells Inhibits Pulmonary Tumorigenesis

Abstract

The Forkhead Box m1 (Foxm1) protein is induced in a majority of human non-small cell lung cancers and its expression is associated with poor prognosis. However, specific requirements for the Foxm1 in each cell type of the cancer lesion remain unknown. The present study provides the first genetic evidence that the Foxm1 expression in respiratory epithelial cells is essential for lung tumorigenesis. Using transgenic mice, we demonstrated that conditional deletion of Foxm1 from lung epithelial cells (epFoxm1−/− mice) prior to tumor initiation caused a striking reduction in the number and size of lung tumors, induced by either urethane or 3-methylcholanthrene (MCA)/butylated hydroxytoluene (BHT). Decreased lung tumorigenesis in epFoxm1−/− mice was associated with diminished proliferation of tumor cells and reduced expression of Topoisomerase-2α (TOPO-2α), a critical regulator of tumor cell proliferation. Depletion of Foxm1 mRNA in cultured lung adenocarcinoma cells significantly decreased TOPO-2α mRNA and protein levels. Moreover, Foxm1 directly bound to and induced transcription of the mouse TOPO-2α promoter region, indicating that TOPO-2α is a direct target of Foxm1 in lung tumor cells. Finally, we demonstrated that a conditional deletion of Foxm1 in pre-existing lung tumors dramatically reduced tumor growth in the lung. Expression of Foxm1 in respiratory epithelial cells is critical for lung cancer formation and TOPO-2α expression in vivo, suggesting that Foxm1 is a promising target for anti-tumor therapy.

The same, only different – DNA damage checkpoints and their reversal throughout the cell cycle

“…Consistent with this is the finding that positive regulators of checkpoint recovery in G2 are commonly overexpressed in cancer and associated with poor prognosis (Bulavin et al, 2002;Cholewa et al, 2013;Li et al, 2002;Wang et al, 2008;Wierstra, 2013). Conversely, tumorigenesis is impaired in their absence (Bulavin et al, 2004;Wang et al, 2009), and several regulators of G2 checkpoint recovery are under (pre)clinical evaluation (Gilmartin et al, 2014;Gumireddy et al, 2005;Stadler et al, 2014). Understanding the mechanisms underlying cellular fate will allow us to devise new therapeutic strategies to sensitise cancer cells to DNA-damaging agents currently used in the clinic.…”

FOXM1 Promotes Allergen-Induced Goblet Cell Metaplasia and Pulmonary Inflammation

“…FOXM1 inactivation in cycling cells caused delays in DNA replication and mitosis, and altered expression of cell cycle regulatory genes (20)(21)(22)(23). Consistent with an important role of FOXM1 in cell cycle progression, FOXM1 induced proliferation of tumor cells during development of lung, liver, brain, and prostate cancers (21,(24)(25)(26)(27). Likewise, FOXM1 accelerated cellular proliferation during acute lung and liver injuries (28,29).…”

“…Lungs were inflated, fixed in 4% paraformaldehyde, and embedded in paraffin blocks. Five-m sections were stained with hematoxylin and eosin (H&E) or Alcian blue or used for immunohistochemistry as described previously (26,31,43). The following antibodies were used for immunostaining: FOXM1 (1:1,000, K-19, sc500; Santa Cruz Biotechnology), Cre recombinase (1:15,000, 69050-3; Novagen), Clara cell-secreted protein (CCSP; 1:2,000, WRAB-CCSP; Seven Hill Bioreagents), Ki-67 (1:500, clone Tec-3; Dako), PH3 (1:500, sc8656r; Santa Cruz Biotechnology), FOXA2 (1:4,000, WRAB-FoxA2; Seven Hills Bioreagents); FOXA3 (1:200, sc5361; Santa Cruz Biotechnology), ␤-tubulin (1:100, MU178-UC, BioGenex), SPDEF (1:2,000; generated in the lab of J.…”

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

“…Recent research has validated the critical role of FOXM1 protein in tumorgenesis. Wang [20] showed that FOXM1 is associated with poor prognosis of non-small cell lung cancer (NSCLC). 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.…”