ArticleExperimental & molecular medicine2023
The tobacco-specific carcinogen NNK induces pulmonary tumorigenesis via nAChR/Src/STAT3-mediated activation of the renin-angiotensin system and IGF-1R signaling.
Article in Experimental & molecular medicine, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 12 papers.
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Who cites it
12 citing papers in PubMed, 20 citations in OpenAlex.
- A malignant symbiosis: The neuro-metabolic symphony rewires the tumor microenvironment.Neoplasia (New York, N.Y.) · 2026Review
- Exposure-informed lung transcriptomic analysis links predicted NNK targets to cell type-specific remodeling programs in idiopathic pulmonary fibrosis.Functional & integrative genomics · 2026Article
- Deep learning model and omics screening highlight angiotensinogen as a 5-methylcytosine (mFrontiers in immunology · 2026Article
- hsa-let-7b-5p-associated BUB1/TMPO-AS1 ceRNA axis identified as a potential biomarker in lung adenocarcinoma.Cell division · 2025Article
- The IGF Signalling Axis in Lung Cancer: Clinical Significance and Therapeutic Challenges.Journal of cellular and molecular medicine · 2025Article
- Smoking-Associated Carcinogen-Induced Inflammation Promotes Lung Carcinogenesis via IRAK4 Activation.Clinical cancer research : an official journal of the American Association for Cancer Research · 2025Article
- 1p-Enh-regulated CYP4B1 alleviates NNK-induced heart failure and lung cancer via the STAT3 pathway.PloS one · 2025Article
- Development and Validation of an AI-Driven System for Automatic Literature Analysis and Molecular Regulatory Network Construction.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Review
- Article
- Role of Insulin-like Growth Factor-1 Receptor in Tobacco Smoking-Associated Lung Cancer Development.Biomedicines · 2024Review
- Hypermethylation of the ADIRF promoter regulates its expression level and is involved in NNK-induced malignant transformation of lung bronchial epithelial cells.Archives of toxicology · 2023Article
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Authors and funding
10 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
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.
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