Role of NKX2-1 in N-bis(2-hydroxypropyl)-nitrosamine-induced thyroid adenoma in mice

Hoshi, Seiji; Hoshi, Nobuo; Okamoto, Minoru; Paiz, Jorge; Kusakabe, Takashi; Ward, Jerrold M.; Kimura, Shioko

doi:10.1093/carcin/bgp167

Cited by 16 publications

(9 citation statements)

References 37 publications

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“…Recent studies using lung cancer mouse models did not support the proposed role of NKX2-1 as a tissue-specific oncogene, but rather implicated NKX2-1 as an antimetastatic factor (10,11). Furthermore, reduced expression of Nkx2-1 induced cell proliferation and promoted carcinogen-induced thyroid adenoma in vivo (47). In the present study, NKX2-1 suppressed Kras tumorigenesis, but promoted EGFR tumorigenesis, in the transgenic mouse models.…”

Section: Methodscontrasting

confidence: 84%

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

Maeda

Tsuchiya

Hao³

et al. 2012

J. Clin. Invest.

141

198

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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. IntroductionMucinous adenocarcinoma of the lung (formerly known as mucinous bronchioalveolar cancer) is pathologically classified as tumor cells with goblet cell morphology containing abundant intracytoplasmic mucin (1). Invasive mucinous adenocarcinoma of the lung has a higher malignant potential than do the more common types of lung adenocarcinoma, such as acinar or papillary adenocarcinoma. Mucinous adenocarcinoma of the lung is associated with decreased or absent expression of the transcription factor NK2 homeobox 1 (NKX2-1; also known as TTF-1) and the expression of mucins, including mucin 5AC, oligomeric mucus/gel-forming (MUC5AC). Genetically, approximately 76% of mucinous adenocarcinomas of the lung have KRAS mutations, a frequent mutation in lung adenocarcinoma associated with tobacco use (2), but mucinous adenocarcinoma of the lung is rarely associated with EGFR mutations. In contrast, nonmucinous lung adenocarcinoma is frequently associated with EGFR mutations (∼45%), but less frequently with KRAS mutations (∼13%; ref. 1).NKX2-1 plays a critical role in lung morphogenesis and respiratory epithelial-specific gene expression, including activation of surfactant proteins and repression of mucins (3, 4). The potential oncogenic role of NKX2-1 in the pathogenesis of adenocarcinoma of the lung was proposed by findings that a region of 14q13.3 containing NKX2-1, NKX2-8, and PAX9 was amplified in approximately 10% of human lung adenocarcinoma (5-7). Loss-offunction and gain-of-function studies in human lung carcinoma and transformed cells supporte...

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Section: Methodscontrasting

confidence: 84%

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

Maeda

Tsuchiya

Hao³

et al. 2012

J. Clin. Invest.

141

198

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“…Thus, Nkx2-1 loss augments tumor burden predominantly by increasing the number of lesions initiated by Kras G12D . Of note, tissue-specific Nkx2-1 deletion also enhances chemically-induced thyroid tumorigenesis (Hoshi et al, 2009). …”

Section: Resultsmentioning

confidence: 99%

Nkx2-1 Represses a Latent Gastric Differentiation Program in Lung Adenocarcinoma

et al. 2013

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SUMMARY Tissue-specific differentiation programs become dysregulated during cancer evolution. The transcription factor Nkx2-1 is a master regulator of pulmonary differentiation that is downregulated in poorly differentiated lung adenocarcinoma. Here we use conditional murine genetics to determine how the identity of lung epithelial cells changes upon loss of their master cell fate regulator. Nkx2-1 deletion in normal and neoplastic lung causes not only loss of pulmonary identity but also conversion to a gastric lineage. Nkx2-1 is likely to maintain pulmonary identity by recruiting transcription factors Foxa1 and Foxa2 to lung-specific loci thus preventing them from binding gastrointestinal targets. Nkx2-1-negative murine lung tumors mimic mucinous human lung adenocarcinomas, which express gastric markers. Loss of the gastrointestinal transcription factor Hnf4α leads to de-repression of the embryonal protoncogene Hmga2 in Nkx2-1-negative tumors. These observations suggest that loss of both active and latent differentiation programs is required for tumors to reach a primitive, poorly differentiated state.

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“…NKX2-1 encodes thyroid transcription factor 1 (TTF1), a key regulator of thyroid, lung, and brain morphogenesis (23). A relationship between reduced expression of Nkx2-1 and thyroid tumors was established in Nkx2-1 thyroid-conditional-hypomorphic mice treated with a nitrosamine-based carcinogen followed by sulfadimethoxine as a promoter, in which an increased incidence of FA was observed (24). In humans, our analysis showed no evidence of a correlation between rs944289 and NKX2-1, and of differential expression of the gene in normal and PTC tissues, indicating that this SNP is unlikely to point at NKX2-1 as at a risk factor for thyroid tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

The Common Genetic Variant rs944289 on Chromosome 14q13.3 Associates with Risk of Both Malignant and Benign Thyroid Tumors in the Japanese Population

Rogounovitch

Bychkov

Takahashi

et al. 2015

Thyroid

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Role of NKX2-1 in N-bis(2-hydroxypropyl)-nitrosamine-induced thyroid adenoma in mice

Cited by 16 publications

References 37 publications

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

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

Nkx2-1 Represses a Latent Gastric Differentiation Program in Lung Adenocarcinoma

The Common Genetic Variant rs944289 on Chromosome 14q13.3 Associates with Risk of Both Malignant and Benign Thyroid Tumors in the Japanese Population

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