title: Foxm1 transcription factor is required for the initiation of lung tumorigenesis by oncogenic Kras(G12D.).
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 Kras(G12D) 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 Kras(G12D) 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 Kras(G12D)-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.
authors.affiliation: 1] Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA [2] Department of Life Sciences, National Tsing Hua University, Hsinchu, Taiwan [3] Institute of Biotechnology, National Tsing Hua University, Hsinchu, Taiwan.
authors.forename: I-C
authors.initials: IC
authors.lastname: Wang
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
authors.forename: V
authors.initials: V
authors.lastname: Ustiyan
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Cai
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
authors.forename: T V
authors.initials: TV
authors.lastname: Kalin
authors.affiliation: Division of Pulmonary Biology, Perinatal Institute of Cincinnati Children's Hospital Research Foundation, Cincinnati, OH, USA.
authors.forename: V V
authors.initials: VV
authors.lastname: Kalinichenko
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D015153:Blotting, Western; D063646:Carcinogenesis / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D004317:Doxorubicin / Q000494:pharmacology; D004848:Epithelium / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D016328:NF-kappa B / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D011485:Protein Binding; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000903:Antibiotics, Antineoplastic; D000072278:Forkhead Box Protein M1; D051858:Forkhead Transcription Factors; C491524:Foxm1 protein, mouse; D016328:NF-kappa B; D004317:Doxorubicin; D048031:JNK Mitogen-Activated Protein Kinases; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)