deletion of forkhead box m1 transcription factor from respiratory epithelial cells inhibits pulmonary tumorigenesis删除forkhead盒子从呼吸道上皮细胞m1转录因子抑制肺肿瘤发生.pdfVIP

Deletion of Forkhead Box M1 Transcription Factor from Respiratory Epithelial Cells Inhibits Pulmonary Tumorigenesis 1 2 1 1 1 1 I-Ching Wang , Lucille Meliton , Xiaomeng Ren , Yufang Zhang , David Balli , Jonathan Snyder , 1 1 1 Jeffrey A. Whitsett , Vladimir V. Kalinichenko *, Tanya V. Kalin * 1 Division of Pulmonary Biology and the Perinatal Institute, Cincinnati Children’s Hospital Research Foundation, Cincinnati, Ohio, United States of America, 2 Department of Medicine, University of Chicago, Chicago, Illinois, United States of America 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 (epFoxm12/ 2 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 epFoxm12/ 2 mice was associated with diminished proliferation of tumor cells and reduced expression of Topoisomerase-2a (TOPO-2a), a critical regulator of tumor cell proliferation. Depletion of Foxm1 mRNA in cultured lung adenocarcinoma cells significantly decreased TOPO-2a mRNA and protein levels. Moreover, Fo