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Transgenic expression of the forkhead box M1 transcription factor induces formation of lung tumors

Oncogene volume 27, pages 4137–4149 (2008)Cite this article

Abstract

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.

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Acknowledgements

We thank S Ramakrishna and IM Kim for technical help, Lloyd Graf for useful comments and Jane Costa for editorial assistance. This work was supported by the Research Grant 06-09 from the American Cancer Society, Illinois Division (VVK), US Public Health Service Grant DK 54687-06 (RHC) and Research Scholar Grant RSG-06-187-01 from the American Cancer Society, National office (VVK).

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Authors and Affiliations

  1. Division of Pulmonary Biology, Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA

    I-C Wang, V V Kalinichenko & T V Kalin

  2. Department of Medicine, University of Chicago, Chicago, IL, USA

    L Meliton

  3. Department of Pathology, University of Chicago, Chicago, IL, USA

    M Tretiakova

  4. Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, USA

    R H Costa

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  1. I-C Wang
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Correspondence to T V Kalin.

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Wang, IC., Meliton, L., Tretiakova, M. et al. Transgenic expression of the forkhead box M1 transcription factor induces formation of lung tumors. Oncogene 27, 4137–4149 (2008). https://doi.org/10.1038/onc.2008.60

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