KrasG12D and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung

Autor: David H. Tompkins, Angela R. Keiser, Tomoshi Tsuchiya, Jeffrey A. Whitsett, Yutaka Maeda, Haiping Hao, Lingling Du, Takuya Fukazawa, Takeshi Nagayasu, Yoshio Naomoto, Yan Xu, Michael L. Mucenski
Jazyk: angličtina
Rok vydání: 2012
Předmět:
Lung Neoplasms
Thyroid Nuclear Factor 1
Mice
Transgenic
Haploinsufficiency
medicine.disease_cause
Urethane
Proto-Oncogene Proteins p21(ras)
Mice
Cell Line
Tumor
Gene expression
Consensus Sequence
medicine
Adenocarcinoma of the lung
Animals
Humans
Promoter Regions
Genetic
Transcription factor
Oligonucleotide Array Sequence Analysis
Binding Sites
biology
Base Sequence
Proto-Oncogene Proteins c-ets
Pulmonary Surfactant-Associated Protein A
Nuclear Proteins
General Medicine
Neoplasms
Experimental
respiratory system
medicine.disease
Adenocarcinoma
Mucinous
Tumor Burden
ErbB Receptors
Gene Expression Regulation
Neoplastic
Transcription Factor AP-1
Cell Transformation
Neoplastic
Amino Acid Substitution
Tumor progression
biology.protein
Cancer research
KRAS
Goblet Cells
Carcinogenesis
Transcriptome
Hepatocyte Nuclear Factor 3-gamma
NK2 homeobox 1
Research Article
Transcription Factors
Popis: 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.
Databáze: OpenAIRE
Externí odkaz: