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Foxm1 transcription factor is required for the initiation of lung tumorigenesis by oncogenic KrasG12D

Oncogene volume 33, pages 5391–5396 (2014)Cite this article

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Abstract

Lung cancer is the leading cause of deaths in cancer patients in the United States. Identification of new molecular targets is clearly needed to improve therapeutic outcomes of this devastating human disease. Activating mutations in K-Ras oncogene and increased expression of FOXM1 protein are associated with poor prognosis in patients with non-small-cell lung cancer. Transgenic expression of activated KrasG12D in mouse respiratory epithelium is sufficient to induce lung adenocarcinomas; however, transcriptional mechanisms regulated by K-Ras during the initiation of lung cancer remain poorly understood. Foxm1 transcription factor, a downstream target of K-Ras, stimulates cellular proliferation during embryogenesis, organ repair and tumor growth, but its role in tumor initiation is unknown. In the present study, we used transgenic mice expressing KrasG12D under control of Sftpc promoter to demonstrate that Foxm1 was induced in type II epithelial cells before the formation of lung tumors. Conditional deletion of Foxm1 from KrasG12D-expressing respiratory epithelium prevented the initiation of lung tumors in vivo. The loss of Foxm1 inhibited expression of K-Ras target genes critical for the nuclear factor-κB (NF-κB) and c-Jun N-terminal kinase (JNK) pathways, including Ikbkb, Nfkb1, Nfkb2, Rela, Jnk1, N-Myc, Pttg1 and Cdkn2a. Transgenic overexpression of activated FOXM1 mutant was sufficient to induce expression of these genes in alveolar type II cells. FOXM1 directly bound to promoter regions of Ikbkb, Nfkb2, N-Myc, Pttg1 and Cdkn2a, indicating that these genes are direct FOXM1 targets. FOXM1 is required for K-Ras-mediated lung tumorigenesis by activating genes critical for the NF-κB and JNK pathways.

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Abbreviations

Cre:

Cre recombinase

Dox:

doxycycline

Fox:

Forkhead Box transcription factor

NF-κB:

nuclear factor-κB

NSCLC:

non-small-cell lung cancer.

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Acknowledgements

We thank Ron Pratt for technical support with microCT imaging and Craig Bolte for helpful comments. This work was supported by NIH grants HL84151 (VVK) and CA142724 (TVK), the Career Development Award from National Lung Cancer Partnership (I-CW), research grants from National Science Council of Taiwan 102B0023V8 (I-CW) and Toward World-Class University Project of National Tsing Hua University 102N2052E1 (I-CW).

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Authors and Affiliations

  1. Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children’s Hospital Research Foundation, Cincinnati, OH, USA

    I-C Wang, V Ustiyan, Y Zhang, Y Cai, T V Kalin & V V Kalinichenko

  2. Department of Life Sciences, National Tsing Hua University, Hsinchu, Taiwan

    I-C Wang

  3. Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan

    I-C Wang

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  1. I-C Wang
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Correspondence to V V Kalinichenko.

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Wang, IC., Ustiyan, V., Zhang, Y. et al. Foxm1 transcription factor is required for the initiation of lung tumorigenesis by oncogenic KrasG12D. Oncogene 33, 5391–5396 (2014). https://doi.org/10.1038/onc.2013.475

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