KrasG12D and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung
Open accessAbstract
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. Results Haploinsufficiency of Nkx2-1 induced mucinous adenocarcinomas during Kras G12D tumorigenesis.In order to determine whether reduced expression of Nkx2-1 influences the pathogenesis of invasive mucinous adenocarcinoma of the lung, we created a mouse model Conflict of interest:The authors have declared that no conflict of interest exists.
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NKX2-1 transactivates ROR1.
“NKX2–1 transactivates the receptor ROR1”
From Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy (2019) · cites this paper as [126]
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Co-occurring genomic alterations in non-small-cell lung cancer biology and therapy
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- Authors
- Maeda, Y., Tsuchiya, T., Hao, H., Tompkins, D. H., Xu, Y., Mucenski, M. L., Du, L., Keiser, A. R., Fukazawa, T., Naomoto, Y., Nagayasu, T., & Whitsett, J. A.
- Affiliations
- Cincinnati Children's Hospital Medical Center (US)
- Nagasaki University (JP)
- Johns Hopkins University (US)
- Kawasaki Medical School (JP)
- Corresponding author
- Whitsett, Jeffrey A.
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 2012-11-12
- Volume
- 122
- Issue
- 12
- Pages
- 4388-4400
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC3533546
- OpenAlex
- W2086620944
- Cited by
- 163
- References
- 58
- Citations by year
- 2026: 4 · 2025: 6 · 2024: 9 · 2023: 21 · 2022: 10 · 2021: 16 · 2020: 8 · 2019: 13 · 2018: 11 · 2017: 16 · 2016: 10 · 2015: 17 · 2014: 9 · 2013: 12 · 2012: 1
- FWCI
- 10.05
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- University of Cincinnati
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL108907, HL095580, U01HL110964, R01HL108907, HL105433, R01HL095580, HL110964, R01HL105433)
- Topics
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Treatments and Mutations
- Health Sciences › Medicine › Oncology › Lung Cancer Research Studies
- Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Lung Cancer Diagnosis and Treatment
- Keywords
- mucinous adenocarcinoma, lung cancer, TTF-1, KRAS G12D, haploinsufficiency, L858R mutation, transcription factors, tumor suppressor, goblet cells, AP-1, chromatin binding, tumor progression, chronic lung disease, transgenic mouse model
- MeSH terms
- Thyroid Nuclear Factor 1, Animals, Base Sequence, Binding Sites, Adenocarcinoma, Mucinous, Cell Transformation, Neoplastic, Humans, Lung Neoplasms, Mice, Transgenic, Neoplasms, Experimental, Nuclear Proteins, Promoter Regions, Genetic, Transcription Factors, Urethane, Gene Expression Regulation, Neoplastic, Proto-Oncogene Proteins p21(ras), Consensus Sequence, Transcription Factor AP-1, Amino Acid Substitution, Goblet Cells, Oligonucleotide Array Sequence Analysis, Pulmonary Surfactant-Associated Protein A, Cell Line, Tumor, Tumor Burden, Proto-Oncogene Proteins c-ets, Mice, Hepatocyte Nuclear Factor 3-gamma, Haploinsufficiency, Transcriptome, ErbB Receptors
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