title: Kras(G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung.
abstract: 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.affiliation: 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.
authors.forename: Yutaka
authors.initials: Y
authors.lastname: Maeda
authors.forename: Tomoshi
authors.initials: T
authors.lastname: Tsuchiya
authors.forename: Haiping
authors.initials: H
authors.lastname: Hao
authors.forename: David H
authors.initials: DH
authors.lastname: Tompkins
authors.forename: Yan
authors.initials: Y
authors.lastname: Xu
authors.forename: Michael L
authors.initials: ML
authors.lastname: Mucenski
authors.forename: Lingling
authors.initials: L
authors.lastname: Du
authors.forename: Angela R
authors.initials: AR
authors.lastname: Keiser
authors.forename: Takuya
authors.initials: T
authors.lastname: Fukazawa
authors.forename: Yoshio
authors.initials: Y
authors.lastname: Naomoto
authors.forename: Takeshi
authors.initials: T
authors.lastname: Nagayasu
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Whitsett
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics*; D019943:Amino Acid Substitution; D000818:Animals; D001483:Base Sequence; D001665:Binding Sites; D045744:Cell Line, Tumor; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D016384:Consensus Sequence; D066246:ErbB Receptors / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic; D020397:Goblet Cells / Q000378:metabolism / Q000473:pathology; D057895:Haploinsufficiency; D051543:Hepatocyte Nuclear Factor 3-gamma / Q000378:metabolism; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced / Q000235:genetics* / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000473:pathology; D009687:Nuclear Proteins / Q000172:deficiency / Q000235:genetics*; D020411:Oligonucleotide Array Sequence Analysis; D011401:Promoter Regions, Genetic; D050783:Proto-Oncogene Proteins c-ets / Q000378:metabolism; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D037662:Pulmonary Surfactant-Associated Protein A / Q000235:genetics; D000074482:Thyroid Nuclear Factor 1; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014157:Transcription Factors / Q000172:deficiency / Q000235:genetics*; D059467:Transcriptome; D047368:Tumor Burden; D014520:Urethane
chemical_list: C496506:Foxa3 protein, mouse; C000614412:NKX2-1 protein, human; C000614414:Nkx2-1 protein, mouse; D009687:Nuclear Proteins; D050783:Proto-Oncogene Proteins c-ets; D037662:Pulmonary Surfactant-Associated Protein A; C519908:Spdef protein, mouse; D000074482:Thyroid Nuclear Factor 1; D018808:Transcription Factor AP-1; D014157:Transcription Factors; D051543:Hepatocyte Nuclear Factor 3-gamma; D014520:Urethane; D066246:ErbB Receptors; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)