|Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung.|
|PMID: 23143308 Owner: NLM Status: MEDLINE|
|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.|
|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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|Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Date: 2012-11-12|
|Title: The Journal of clinical investigation Volume: 122 ISSN: 1558-8238 ISO Abbreviation: J. Clin. Invest. Publication Date: 2012 Dec|
|Created Date: 2012-12-03 Completed Date: 2013-02-04 Revised Date: 2014-03-07|
Medline Journal Info:
|Nlm Unique ID: 7802877 Medline TA: J Clin Invest Country: United States|
|Languages: eng Pagination: 4388-400 Citation Subset: AIM; IM|
|APA/MLA Format Download EndNote Download BibTex|
Amino Acid Substitution
Cell Line, Tumor
Cell Transformation, Neoplastic / genetics
Gene Expression Regulation, Neoplastic
Goblet Cells / metabolism, pathology
Hepatocyte Nuclear Factor 3-gamma / metabolism
Lung Neoplasms / chemically induced, genetics*, pathology
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*
|HL095580/HL/NHLBI NIH HHS; HL105433/HL/NHLBI NIH HHS; HL108907/HL/NHLBI NIH HHS; HL110964/HL/NHLBI NIH HHS; R01 HL095580/HL/NHLBI NIH HHS; R01 HL105433/HL/NHLBI NIH HHS|
|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; 3IN71E75Z5/Urethane; EC 126.96.36.199/Receptor, Epidermal Growth Factor; EC 188.8.131.52/Kras2 protein, mouse; EC 184.108.40.206/Proto-Oncogene Proteins p21(ras)|
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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