Increased expression of FoxM1 transcription factor in respiratory epithelium inhibits lung sacculation and causes Clara cell hyperplasia

Division of Pulmonary Biology, Perinatal Institute of the Cincinnati Children's Hospital Research Foundation, 3333 Burnet Ave., Cincinnati, OH 45229, USA.
Developmental Biology (Impact Factor: 3.55). 11/2010; 347(2):301-14. DOI: 10.1016/j.ydbio.2010.08.027
Source: PubMed


Foxm1 is a member of the Forkhead Box (Fox) family of transcription factors. Foxm1 (previously called Foxm1b, HFH-11B, Trident, Win, or MPP2) is expressed in multiple cell types and plays important roles in cellular proliferation, differentiation and tumorigenesis. Genetic deletion of Foxm1 from mouse respiratory epithelium during initial stages of lung development inhibits lung maturation and causes respiratory failure after birth. However, the role of Foxm1 during postnatal lung morphogenesis remains unknown. In the present study, Foxm1 expression was detected in epithelial cells of conducting and peripheral airways and changing dynamically with lung maturation. To discern the biological role of Foxm1 in the prenatal and postnatal lung, a novel transgenic mouse line that expresses a constitutively active form of FoxM1 (FoxM1 N-terminal deletion mutant or FoxM1-ΔN) under the control of lung epithelial-specific SPC promoter was produced. Expression of the FoxM1-ΔN transgene during embryogenesis caused epithelial hyperplasia, inhibited lung sacculation and expression of the type II epithelial marker, pro-SPC. Expression of FoxM1-ΔN mutant during the postnatal period did not influence alveologenesis but caused focal airway hyperplasia and increased proliferation of Clara cells. Likewise, expression of FoxM1-ΔN mutant in conducting airways with Scgb1a1 promoter was sufficient to induce Clara cell hyperplasia. Furthermore, FoxM1-ΔN cooperated with activated K-Ras to induce lung tumor growth in vivo. Increased activity of Foxm1 altered lung sacculation, induced proliferation in the respiratory epithelium and accelerated lung tumor growth, indicating that precise regulation of Foxm1 is critical for normal lung morphogenesis and development of lung cancer.

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Available from: I-Ching Wang, May 02, 2014
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    • "Authors have well documented that FOXM1 plays an important role in the development and progression of PDAC and that FOXM1 overexpression is associated with poor prognosis and advanced clinicopathologic stages of PDAC [22]. Recent studies using human and mammalian models revealed that FOXM1 has a role in promotion of tumorigenesis by stimulating stem cell-like characteristics in pancreatic cancer cells, including self-renewal capacity [15,72,75]. Accordingly, a lung tumorigenesis study demonstrated that overexpression of FOXM1 promoted Clara cell hyperplasia and cooperated with activated K-Ras to induce lung cancer development in vivo[72]. "
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    ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) has one of the poorest prognoses among all cancers. Over the past several decades, investigators have made great advances in the research of PDAC pathogenesis. Importantly, identification of pancreatic cancer stem cells (PCSCs) in pancreatic cancer cases has increased our understanding of PDAC biology and therapy. PCSCs are responsible for pancreatic tumorigenesis and tumor progression via a number of mechanisms, including extensive proliferation, self-renewal, high tumorigenic ability, high propensity for invasiveness and metastasis, and resistance to conventional treatment. Furthermore, emerging evidence suggests that PCSCs are involved in the malignant transformation of pancreatic intraepithelial neoplasia. The molecular mechanisms that control PCSCs are related to alterations of various signaling pathways, for instance, Hedgehog, Notch, Wnt, B-cell-specific Moloney murine leukemia virus insertion site 1, phosphoinositide 3-kinase/AKT, and Nodal/Activin. Also, authors have reported that the proliferation-specific transcriptional factor Forkhead box protein M1 is involved in PCSC self-renewal and proliferation. In this review, we describe the current knowledge about the signaling pathways related to PCSCs and the early stages of PDAC development, highlighting the pivotal roles of Forkhead box protein M1 in PCSCs and their impacts on the development and progression of pancreatic intraepithelial neoplasia.
    Molecular Cancer 12/2013; 12(1):159. DOI:10.1186/1476-4598-12-159 · 4.26 Impact Factor
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    • "In the present study, we revealed that the expression of FoxM1 mRNA had a significant increasing tendency during the prenatal period. This is consistent with a recent mouse study by Wang, et al.,30 even though the postnatal change in FoxM1 expression differed from the present study. They found that the expression of FoxM1 was reactivated just after birth and rapidly decreased at day 10 of the postnatal period, while no significant change was found in the FoxM1 expression levels just before and after birth in the present study. "
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    ABSTRACT: Purpose Recently, Forkhead box M1 (FoxM1) was reported to be correlated with lung maturation and expression of surfactant proteins (SPs) in mice models. However, no study has been conducted in rabbit lungs despite their high homology with human lungs. Thus, we attempted to investigate serial changes in the expressions of FoxM1 and SP-A/B throughout lung maturation in rabbit fetuses. Materials and Methods Pregnant New Zealand White rabbits were grouped according to gestational age from 5 days before to 2 days after the day of expected full term delivery (F5, F4, F3, F2, F1, F0, P1, and P2). A total of 64 fetuses were enrolled after Cesarean sections. The expressions of mRNA and proteins of FoxM1 and SP-A/B in fetal lung tissue were tested by quantitative reverse-transcriptase real-time PCR and Western blot. Furthermore, their correlations were analyzed. Results The mRNA expression of SP-A/B showed an increasing tendency positively correlated with gestational age, while the expression of FoxM1 mRNA and protein decreased from F5 to F0. A significant negative correlation was found between the expression levels of FoxM1 and SP-A/B (SP-A: R=-0.517, p=0.001; SP-B: R=-0.615, p<0.001). Conclusion Preterm rabbits demonstrated high expression of FoxM1 mRNA and protein in the lungs compared to full term rabbits. Also, the expression of SP-A/B was inversely related with serial changes in FoxM1 expression. This is the first report to suggest an association between FoxM1 and expression of SP-A/B and lung maturation in preterm rabbits.
    Yonsei medical journal 11/2013; 54(6):1422-9. DOI:10.3349/ymj.2013.54.6.1422 · 1.29 Impact Factor
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    • "Diagnosis was done according to the American Thoracic Society/European Respiratory Society (ATS/ ERS) criteria for IPF. The generation of transgenic SP-C–rtTA tg/ À / tetO-Foxm1-DN tg/ À (epiFoxm1-DN) mice and SP-C–rtTA tg/ À / TetO-Cre tg/ À /Foxm1 fl/fl (SP-C–rtTA tg/ À / TetO-Cre tg/ À /Foxm1 fl/fl (epiFoxm1 KO or epiFoxm1 KO) mice have been described previously (Kalin et al, 2008b; Wang et al, 2010). The epiFoxm1- DN mice were maintained in FVBN genetic background. "
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    ABSTRACT: 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-1β, 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.
    The EMBO Journal 01/2013; 32(2). DOI:10.1038/emboj.2012.336 · 10.43 Impact Factor
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