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Article

The Effect of Tobacco Smoke N-Nitrosamines, NNK and NDEA, and Nicotine, on DNA Mismatch Repair Mechanism and miRNA Markers, in Hypopharyngeal Squamous Cell Carcinoma: An In Vivo Model and Clinical Evidence

1
The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA
2
Department of Forensic Sciences and Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece
3
Department of Medicine, Rutgers/Saint Peter’s University Hospital, New Brunswick, NJ 08901, USA
4
Department of Histology & Embryology, Medical School, University of Crete, 71003 Heraklion, Greece
*
Author to whom correspondence should be addressed.
Curr. Oncol. 2022, 29(8), 5531-5549; https://doi.org/10.3390/curroncol29080437
Received: 18 June 2022 / Revised: 22 July 2022 / Accepted: 31 July 2022 / Published: 4 August 2022
(This article belongs to the Special Issue Advances in Squamous Cell Carcinoma of the Head and Neck)
Deregulation of the DNA mismatch repair (MMR) mechanism has been linked to poor prognosis of upper aerodigestive tract cancers. Our recent in vitro data have provided evidence of crosstalk between deregulated miRNAs and MMR genes, caused by tobacco smoke (TS) N-Nitrosamines, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), in hypopharyngeal cells. Here, we explored whether chronic exposure to TS components can affect MMR mechanism and miRNA profiles in hypopharyngeal mucosa. Using a mouse model (C57Bl/6J wild type) of in vivo 14-week exposure to NNK (0.2 mmol/L) and N-Nitrosodiethylamine (NDEA; 0.004 mmol/L), with or without nicotine (0.02 μmol/L), we provide direct evidence that TS components can promote dysplasia, significant downregulation of Msh2 and Mlh1 genes and deregulation of miR-21, miR-155, miR-34a, and miR-451a. By analyzing eight human specimens from tobacco smokers and eight controls, we provide clinical evidence of a significant reduction in hMSH2 and hMLH1 mRNAs in hypopharyngeal squamous cell carcinoma (HSCC). In summary, deregulation of the MMR mechanism and miRNAs is caused by chronic exposure to TS-related N-Nitrosamines, with or without nicotine, in the early stages of upper aerodigestive tract carcinogenesis, and can also be detected in human HSCC. Thus, we encourage future studies to further elucidate a possible in vivo dose-dependent effect of individual or combined N-Nitrosamines, NNK and/or NDEA, and nicotine, on the MMR mechanism and their clinical testing to elaborate prognosis and risk assessment. View Full-Text
Keywords: DNA mismatch repair; tobacco smoke; N-Nitrosamines; NNK; NDEA; nicotine; MSH2; MLH1; human hypopharyngeal squamous cell carcinoma; head and neck cancer DNA mismatch repair; tobacco smoke; N-Nitrosamines; NNK; NDEA; nicotine; MSH2; MLH1; human hypopharyngeal squamous cell carcinoma; head and neck cancer
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MDPI and ACS Style

Doukas, S.G.; Vageli, D.P.; Doukas, P.G.; Nikitovic, D.; Tsatsakis, A.; Judson, B.L. The Effect of Tobacco Smoke N-Nitrosamines, NNK and NDEA, and Nicotine, on DNA Mismatch Repair Mechanism and miRNA Markers, in Hypopharyngeal Squamous Cell Carcinoma: An In Vivo Model and Clinical Evidence. Curr. Oncol. 2022, 29, 5531-5549. https://doi.org/10.3390/curroncol29080437

AMA Style

Doukas SG, Vageli DP, Doukas PG, Nikitovic D, Tsatsakis A, Judson BL. The Effect of Tobacco Smoke N-Nitrosamines, NNK and NDEA, and Nicotine, on DNA Mismatch Repair Mechanism and miRNA Markers, in Hypopharyngeal Squamous Cell Carcinoma: An In Vivo Model and Clinical Evidence. Current Oncology. 2022; 29(8):5531-5549. https://doi.org/10.3390/curroncol29080437

Chicago/Turabian Style

Doukas, Sotirios G., Dimitra P. Vageli, Panagiotis G. Doukas, Dragana Nikitovic, Aristidis Tsatsakis, and Benjamin L. Judson. 2022. "The Effect of Tobacco Smoke N-Nitrosamines, NNK and NDEA, and Nicotine, on DNA Mismatch Repair Mechanism and miRNA Markers, in Hypopharyngeal Squamous Cell Carcinoma: An In Vivo Model and Clinical Evidence" Current Oncology 29, no. 8: 5531-5549. https://doi.org/10.3390/curroncol29080437

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