Foxm1 transcription factor is required for lung fibrosis and epithelial-to-mesenchymal transition

• Published in: The EMBO journal Vol. 32; no. 2; pp. 231 - 244
• Main Authors: Balli, David, Ustiyan, Vladimir, Zhang, Yufang, Wang, I-Ching, Masino, Alex J, Ren, Xiaomeng, Whitsett, Jeffrey A, Kalinichenko, Vladimir V, Kalin, Tanya V
• Format: Journal Article
• Language: English
• Published: Chichester, UK John Wiley & Sons, Ltd 23.01.2013; Nature Publishing Group UK; Blackwell Publishing Ltd; Nature Publishing Group
• Subjects: Animals; Cells, Cultured; EMBO09; EMBO24; EMBO37; EMT; Epithelial-Mesenchymal Transition - genetics; Epithelial-Mesenchymal Transition - physiology; Fibrosis - etiology; Fibrosis - genetics; Fibrosis - metabolism; Forkhead Box Protein M1; Forkhead Transcription Factors - genetics; Forkhead Transcription Factors - metabolism; Forkhead Transcription Factors - physiology; Foxm1; Gene expression; Gene Expression Regulation - physiology; Humans; Inflammatory diseases; Irradiation; Lung - metabolism; Lung - pathology; Lung - radiation effects; Lungs; Mice; Mice, Inbred C57BL; Mice, Transgenic; Pneumonia - genetics; Pneumonia - metabolism; Pulmonary Fibrosis - etiology; Pulmonary Fibrosis - genetics; Pulmonary Fibrosis - pathology; pulmonary inflammation; Radiation Injuries, Experimental - genetics; Radiation Injuries, Experimental - metabolism; Radiation Injuries, Experimental - pathology; radiation-induced lung fibrosis; Ribonucleic acid; RNA; Snail1; pulmonary inflammation; radiation‐induced lung fibrosis; EMT; Foxm1; Snail1
• ISSN: 0261-4189; 1460-2075
• DOI: 10.1038/emboj.2012.336

Alveolar epithelial cells (AECs) participate in the pathogenesis of pulmonary fibrosis, producing pro‐inflammatory mediators and undergoing epithelial‐to‐mesenchymal transition (EMT). Herein, we demonstrated the critical role of Forkhead Box M1 (Foxm1) transcription factor in radiation‐induced pulmonary fibrosis. Foxm1 was induced in AECs following lung irradiation. Transgenic expression of an activated Foxm1 transcript in AECs enhanced radiation‐induced pneumonitis and pulmonary fibrosis, and increased the expression of IL‐1 β, Ccl2 , Cxcl5 , Snail1 , Zeb1 , Zeb2 and Foxf1 . Conditional deletion of Foxm1 from respiratory epithelial cells decreased radiation‐induced pulmonary fibrosis and prevented the increase in EMT‐associated gene expression. siRNA‐mediated inhibition of Foxm1 prevented TGF‐β‐induced EMT in vitro . Foxm1 bound to and increased promoter activity of the Snail1 gene, a critical transcriptional regulator of EMT. Expression of Snail1 restored TGF‐β‐induced loss of E‐cadherin in Foxm1‐deficient cells in vitro . Lineage‐tracing studies demonstrated that Foxm1 increased EMT during radiation‐induced pulmonary fibrosis in vivo . Foxm1 is required for radiation‐induced pulmonary fibrosis by enhancing the expression of genes critical for lung inflammation and EMT. This study establishes the in vivo relevance of FoxM1 in the context of radiation‐induced fibrosis. FoxM1 ablation in the respiratory epithelium supports a regulatory role during EMT and pulmonary inflammation that could become of therapeutic relevance.