دورية أكاديمية
The tobacco-specific carcinogen NNK induces pulmonary tumorigenesis via nAChR/Src/STAT3-mediated activation of the renin-angiotensin system and IGF-1R signaling
| العنوان: | The tobacco-specific carcinogen NNK induces pulmonary tumorigenesis via nAChR/Src/STAT3-mediated activation of the renin-angiotensin system and IGF-1R signaling |
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| المؤلفون: | Hye-Jin Boo, Hye-Young Min, Su Jung Hwang, Hyo-Jong Lee, Jae-Won Lee, Sei-Ryang Oh, Choon-Sik Park, Jong-Sook Park, You Mie Lee, Ho-Young Lee |
| المصدر: | Experimental and Molecular Medicine, Vol 55, Iss 6, Pp 1131-1144 (2023) |
| بيانات النشر: | Nature Publishing Group, 2023. |
| سنة النشر: | 2023 |
| المجموعة: | LCC:Medicine LCC:Biochemistry |
| مصطلحات موضوعية: | Medicine, Biochemistry, QD415-436 |
| الوصف: | Abstract The renin-angiotensin (RA) system has been implicated in lung tumorigenesis without detailed mechanistic elucidation. Here, we demonstrate that exposure to the representative tobacco-specific carcinogen nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) promotes lung tumorigenesis through deregulation of the pulmonary RA system. Mechanistically, NNK binding to the nicotinic acetylcholine receptor (nAChR) induces Src-mediated signal transducer and activator of transcription 3 (STAT3) activation, resulting in transcriptional upregulation of angiotensinogen (AGT) and subsequent induction of the angiotensin II (AngII) receptor type 1 (AGTR1) signaling pathway. In parallel, NNK concurrently increases insulin-like growth factor 2 (IGF2) production and activation of IGF-1R/insulin receptor (IR) signaling via a two-step pathway involving transcriptional upregulation of IGF2 through STAT3 activation and enhanced secretion from intracellular storage through AngII/AGTR1/PLC-intervened calcium release. NNK-mediated crosstalk between IGF-1R/IR and AGTR1 signaling promoted tumorigenic activity in lung epithelial and stromal cells. Lung tumorigenesis caused by NNK exposure or alveolar type 2 cell-specific Src activation was suppressed by heterozygous Agt knockout or clinically available inhibitors of the nAChR/Src or AngII/AGTR1 pathways. These results demonstrate that NNK-induced stimulation of the lung RA system leads to IGF2-mediated IGF-1R/IR signaling activation in lung epithelial and stromal cells, resulting in lung tumorigenesis in smokers. |
| نوع الوثيقة: | article |
| وصف الملف: | electronic resource |
| اللغة: | English |
| تدمد: | 2092-6413 |
| Relation: | https://doaj.org/toc/2092-6413 |
| DOI: | 10.1038/s12276-023-00994-2 |
| URL الوصول: | https://doaj.org/article/dc30c8eff1d24fa5b014bc318d4499e6 |
| رقم الأكسشن: | edsdoj.30c8eff1d24fa5b014bc318d4499e6 |
| قاعدة البيانات: | Directory of Open Access Journals |
Find this article in full text from Springer Verlag. 
Full Text Finder | تدمد: | 20926413 |
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| DOI: | 10.1038/s12276-023-00994-2 |