Transgenic expression of the forkhead box M1 transcription factor induces formation of lung tumors.
The forkhead box m1 (Foxm1 or Foxm1b) protein (previously called HFH-11B, Trident, Win or MPP2) is abundantly expressed in human non-small cell lung cancers where it transcriptionally induces expression of genes essential for proliferation of tumor cells. In this study, we used Rosa26-Foxm1 transgenic mice, in which the Rosa26 promoter drives ubiquitous expression of Foxm1 transgene, to identify new signaling pathways regulated by Foxm1. Lung tumors were induced in Rosa26-Foxm1 mice using the 3-methylcholanthrene (MCA)/butylated hydroxytoluene (BHT) lung tumor initiation/promotion protocol. Tumors from MCA/BHT-treated Rosa26-Foxm1 mice displayed a significant increase in the number, size and DNA replication compared to wild-type mice. Elevated tumor formation in Rosa26-Foxm1 transgenic lungs was associated with persistent pulmonary inflammation, macrophage infiltration and increased expression of cyclooxygenase-2 (Cox-2), Cdc25C phosphatase, cyclin E2, chemokine ligands CXCL5, CXCL1 and CCL3, cathepsins and matrix metalloprotease-12. Cell culture experiments with A549 human lung adenocarcinoma cells demonstrated that depletion of Foxm1 by either short interfering RNA transfection or treatment with Foxm1-inhibiting ARF 26-44 peptide significantly reduced Cox-2 expression. In co-transfection experiments, Foxm1 protein-induced Cox-2 promoter activity and directly bound to the -2566/-2580 bp region of human Cox-2 promoter.
Wang
I-C
IC
Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH 45229, USA.
Meliton
L
L
Tretiakova
M
M
Costa
R H
RH
Kalinichenko
V V
VV
Kalin
T V
TV
D000236:Adenoma / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D000818:Animals; D002084:Butylated Hydroxytoluene; D051546:Cyclooxygenase 2 / Q000235:genetics; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D020022:Genetic Predisposition to Disease; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D008748:Methylcholanthrene; D051379:Mice; D008822:Mice, Transgenic; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D014162:Transfection; D047368:Tumor Burden; D014407:Tumor Cells, Cultured
D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D002084:Butylated Hydroxytoluene; D008748:Methylcholanthrene; C077623:Ptgs2 protein, mouse; D051546:Cyclooxygenase 2