{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T04:38:20Z","timestamp":1787027900971,"version":"build-2736575974"},"reference-count":54,"publisher":"MDPI AG","issue":"8","license":[{"start":{"date-parts":[[2022,8,4]],"date-time":"2022-08-04T00:00:00Z","timestamp":1659571200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Virginia Alden Wright Fund"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Current Oncology"],"abstract":"<jats:p>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 \u03bcmol\/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.<\/jats:p>","DOI":"10.3390\/curroncol29080437","type":"journal-article","created":{"date-parts":[[2022,8,4]],"date-time":"2022-08-04T21:52:48Z","timestamp":1659649968000},"page":"5531-5549","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["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"],"prefix":"10.3390","volume":"29","author":[{"given":"Sotirios G.","family":"Doukas","sequence":"first","affiliation":[{"name":"The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA"},{"name":"Department of Forensic Sciences and Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece"},{"name":"Department of Medicine, Rutgers\/Saint Peter\u2019s University Hospital, New Brunswick, NJ 08901, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9852-5790","authenticated-orcid":false,"given":"Dimitra P.","family":"Vageli","sequence":"additional","affiliation":[{"name":"The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8050-963X","authenticated-orcid":false,"given":"Panagiotis G.","family":"Doukas","sequence":"additional","affiliation":[{"name":"The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3882-7399","authenticated-orcid":false,"given":"Dragana","family":"Nikitovic","sequence":"additional","affiliation":[{"name":"Department of Histology & Embryology, Medical School, University of Crete, 71003 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3824-2462","authenticated-orcid":false,"given":"Aristidis","family":"Tsatsakis","sequence":"additional","affiliation":[{"name":"Department of Forensic Sciences and Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin L.","family":"Judson","sequence":"additional","affiliation":[{"name":"The Yale Larynx Laboratory, Department of Surgery, Yale School of Medicine, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,8,4]]},"reference":[{"key":"ref_1","unstructured":"Centers for Disease Control and Prevention (CDC) (2022, March 17). 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