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.
Highlights
Lung cancer is the leading cause of cancer-related deaths in men and women in the United States [1]
Conditional deletion of Forkhead Box m1 (Foxm1) transcription factor in lung epithelial cells To determine the role of Foxm1 in epithelial cells during formation of lung tumors, we generated triple-transgenic mice containing LoxP-flanked exons 4–7 of the Foxm1 gene (Foxm1fl/fl), the SP-C–rtTAtg/2 and the TetO-Cretg/2 transgenes (SP-C–rtTAtg/2/ TetO-Cretg/2/Foxm1fl/fl or epFoxm1fl/fl mice)
Since TOPO-2a is a prominent target for anti-tumor therapy [28] due to its critical role in tumor cell proliferation, we focused our experiments to determine whether TOPO-2a gene is a direct transcriptional target of Foxm1
Summary
Lung cancer is the leading cause of cancer-related deaths in men and women in the United States [1]. It has a high mortality because it is difficult to detect early and is frequently resistant to available chemotherapy and radiotherapy. Adenocarcinoma, the most common type of NSCLC, is frequently associated with gain of function mutations in the K-Ras oncogene [2,3], activation of c-myc protein, as well as the loss of function mutations in the tumor suppressor gene p53 [4,5]. Activating mutations in K-Ras occur in the majority of spontaneous and chemically induced lung tumors in mice [6]
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