Document Detail


Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung.
MedLine Citation:
PMID:  23143308     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
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:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-12
Journal Detail:
Title:  The Journal of clinical investigation     Volume:  122     ISSN:  1558-8238     ISO Abbreviation:  J. Clin. Invest.     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-03     Completed Date:  2013-02-04     Revised Date:  2014-03-19    
Medline Journal Info:
Nlm Unique ID:  7802877     Medline TA:  J Clin Invest     Country:  United States    
Other Details:
Languages:  eng     Pagination:  4388-400     Citation Subset:  AIM; IM    
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MeSH Terms
Descriptor/Qualifier:
Adenocarcinoma, Mucinous / 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:
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; R01 HL108907/HL/NHLBI NIH HHS
Chemical
Reg. No./Substance:
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 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

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