| Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung. | |
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MedLine Citation:
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PMID: 23143308 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Mucinous adenocarcinoma of the lung is a subtype of highly invasive pulmonary tumors and is associated with decreased or absent expression of the transcription factor NK2 homeobox 1 (NKX2-1; also known as TTF-1). Here, we show that haploinsufficiency of Nkx2-1 in combination with oncogenic Kras(G12D), but not with oncogenic EGFR(L858R), caused pulmonary tumors in transgenic mice that were phenotypically similar to human mucinous adenocarcinomas. Gene expression patterns distinguished tumor goblet (mucous) cells from nontumorigenic airway and intestinal goblet cells. Expression of NKX2-1 inhibited urethane and oncogenic Kras(G12D)-induced tumorigenesis in vivo. Haploinsufficiency of Nkx2-1 enhanced Kras(G12D)-mediated tumor progression, but reduced EGFR(L858R)-mediated progression. Genome-wide analysis of gene expression demonstrated that a set of genes induced in mucinous tumors was shared with genes induced in a nontumorigenic chronic lung disease, while a distinct subset of genes was specific to mucinous tumors. ChIP with massively parallel DNA sequencing identified a direct association of NKX2-1 with the genes induced in mucinous tumors. NKX2-1 associated with the AP-1 binding element as well as the canonical NKX2-1 binding element. NKX2-1 inhibited both AP-1 activity and tumor colony formation in vitro. These data demonstrate that NKX2-1 functions in a context-dependent manner in lung tumorigenesis and inhibits Kras(G12D)-driven mucinous pulmonary adenocarcinoma. |
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Authors:
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Yutaka Maeda; Tomoshi Tsuchiya; Haiping Hao; David H Tompkins; Yan Xu; Michael L Mucenski; Lingling Du; Angela R Keiser; Takuya Fukazawa; Yoshio Naomoto; Takeshi Nagayasu; Jeffrey A Whitsett |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-11-12 |
Journal Detail:
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Title: The Journal of clinical investigation Volume: 122 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2012 Dec |
Date Detail:
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Created Date: 2012-12-03 Completed Date: 2013-02-04 Revised Date: 2013-04-26 |
Medline Journal Info:
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Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States |
Other Details:
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Languages: eng Pagination: 4388-400 Citation Subset: AIM; IM |
Affiliation:
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Perinatal Institute, Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children’s Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio 45229-3039, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Adenocarcinoma, Mucinous
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genetics* Amino Acid Substitution Animals Base Sequence Binding Sites Cell Line, Tumor Cell Transformation, Neoplastic / genetics Consensus Sequence Gene Expression Regulation, Neoplastic Goblet Cells / metabolism, pathology Haploinsufficiency* Hepatocyte Nuclear Factor 3-gamma / metabolism Humans Lung Neoplasms / chemically induced, genetics*, pathology Mice Mice, Transgenic Neoplasms, Experimental / chemically induced, genetics, pathology Nuclear Proteins / deficiency, genetics* Oligonucleotide Array Sequence Analysis Promoter Regions, Genetic Proto-Oncogene Proteins c-ets / metabolism Proto-Oncogene Proteins p21(ras) / genetics* Pulmonary Surfactant-Associated Protein A / genetics Receptor, Epidermal Growth Factor / genetics Transcription Factor AP-1 / metabolism Transcription Factors / deficiency, genetics* Transcriptome Tumor Burden Urethane |
| Grant Support | |
ID/Acronym/Agency:
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HL095580/HL/NHLBI NIH HHS; HL105433/HL/NHLBI NIH HHS; HL108907/HL/NHLBI NIH HHS; HL110964/HL/NHLBI NIH HHS; R01 HL105433/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Foxa3 protein, mouse; 0/Nuclear Proteins; 0/Proto-Oncogene Proteins c-ets; 0/Pulmonary Surfactant-Associated Protein A; 0/Spdef protein, mouse; 0/Transcription Factor AP-1; 0/Transcription Factors; 0/thyroid nuclear factor 1; 135845-91-9/Hepatocyte Nuclear Factor 3-gamma; 51-79-6/Urethane; EC 2.7.10.1/Receptor, Epidermal Growth Factor; EC 3.6.5.2/Kras2 protein, mouse; EC 3.6.5.2/Proto-Oncogene Proteins p21(ras) |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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