Information de reference pour ce titreAccession Number: | 00004686-201212000-00015.
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Author: | Maeda, Yutaka 1; Tsuchiya, Tomoshi 2; Hao, Haiping 3; Tompkins, David H. 1; Xu, Yan 1; Mucenski, Michael L. 1; Du, Lingling 1; Keiser, Angela R. 1; Fukazawa, Takuya 4; Naomoto, Yoshio 4; Nagayasu, Takeshi 2; Whitsett, Jeffrey A. 1
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Institution: | (1)Perinatal Institute, Section of Neonatology, Perinatal and Pulmonary Biology, Cincinnati Children's Hospital Medical Center and University of Cincinnati College of Medicine, Cincinnati, Ohio, USA. (2)Division of Surgical Oncology, Department of Translational Medical Sciences, Nagasaki Graduate School of Biomedical Sciences, Nagasaki, Japan. (3)Deep Sequencing and Microarray Core, Johns Hopkins University, Baltimore, Maryland, USA. (4)Department of General Surgery, Kawasaki Medical School, Okayama, Japan.
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Title: | KrasG12D and Nkx2-1 haploinsufficiency induce mucinous adenocarcinoma of the lung .[Article]
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Source: | Journal of Clinical Investigation. 122(12):4388-4400, December 3, 2012.
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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.
Copyright (C) 2012 The American Society for Clinical Investigation, Inc.
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Language: | English.
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Document Type: | Research Article.
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Journal Subset: | Clinical Medicine. Medical Humanities.
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ISSN: | 0021-9738
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NLM Journal Code: | hs7, 7802877
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DOI Number: | https://dx.doi.org/10.1172/JCI64...- ouverture dans une nouvelle fenêtre
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