Kras super( G12D) and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung

• Published in: The Journal of clinical investigation Vol. 122; no. 12; p. 4388
• Main Authors: Maeda, Yutaka, Tsuchiya, Tomoshi, Hao, Haiping, Tompkins, David H, Xu, Yan, Mucenski, Michael L, Du, Lingling, Keiser, Angela R, Fukazawa, Takuya, Naomoto, Yoshio, Nagayasu, Takeshi, Whitsett, Jeffrey A
• Format: Journal Article
• Language: English
• Published: 01.12.2012
• Subjects: Activator protein 1; Adenocarcinoma; Colonies; Data processing; DNA sequencing; Epidermal growth factor receptors; Gene expression; Goblet cells; haploinsufficiency; Homeobox; Intestine; Invasiveness; K-Ras protein; Lung diseases; Respiratory tract; Thyroid transcription factor 1; Transcription factors; Transgenic mice; Tumorigenesis; urethane
• ISSN: 0021-9738

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 super( G12D), but not with oncogenic EGFR super( 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 super( G12D)-induced tumorigenesis in vivo, Haploinsufficiency of Nkx2-1 enhanced Kras super( G12D)-mediated tumor progression, but reduced EGFR super( 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 super( G12D)-driven mucinous pulmonary adenocarcinoma.