KrasG12D and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung
Open Access
- 12 November 2012
- journal article
- research article
- Published by American Society for Clinical Investigation in JCI Insight
- Vol. 122 (12), 4388-4400
- https://doi.org/10.1172/jci64048
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 KrasG12D, but not with oncogenic EGFRL858R, 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 KrasG12D-induced tumorigenesis in vivo. Haploinsufficiency of Nkx2-1 enhanced KrasG12D-mediated tumor progression, but reduced EGFRL858R-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 KrasG12D-driven mucinous pulmonary adenocarcinoma.Keywords
This publication has 58 references indexed in Scilit:
- MYBPH, a transcriptional target of TTF-1, inhibits ROCK1, and reduces cell motility and metastasisThe EMBO Journal, 2011
- Suppression of lung adenocarcinoma progression by Nkx2-1Nature, 2011
- Genome-wide transcription factor binding: beyond direct target regulationTrends in Genetics, 2011
- Integrative genomics viewerNature Biotechnology, 2011
- SOX2 is an amplified lineage-survival oncogene in lung and esophageal squamous cell carcinomasNature Genetics, 2009
- Unique and overlapping gene expression patterns driven by IL-4 and IL-13 in the mouse lungJournal of Allergy and Clinical Immunology, 2009
- Effective use of PI3K and MEK inhibitors to treat mutant Kras G12D and PIK3CA H1047R murine lung cancersNature Medicine, 2008
- An integrated software system for analyzing ChIP-chip and ChIP-seq dataNature Biotechnology, 2008
- Characterizing the cancer genome in lung adenocarcinomaNature, 2007
- LKB1 modulates lung cancer differentiation and metastasisNature, 2007