{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T09:44:48Z","timestamp":1790934288909,"version":"4.1.0"},"reference-count":92,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,21]],"date-time":"2020-04-21T00:00:00Z","timestamp":1587427200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"ELKE grants of Toxicology Lab University of Crete","award":["ELKE No 3550, No 3963, No 4920"],"award-info":[{"award-number":["ELKE No 3550, No 3963, No 4920"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Tobacco smoking is a common risk factor for lung cancer and head and neck cancer. Molecular changes such as deregulation of miRNA expression have been linked to tobacco smoking in both types of cancer. Dysfunction of the Mismatch DNA repair (MMR) mechanism has also been associated with a poor prognosis of these cancers, while a cross-talk between specific miRNAs and MMR genes has been previously proposed. We hypothesized that exposure of lung and head and neck squamous cancer cells (NCI and FaDu, respectively) to tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is capable of altering the expression of MSH2 and MLH1, key MMR components, by promoting specific miRNA deregulation. We found that either a low (1 \u03bcM) or high (2 \u03bcM) dose of NNK induced significant upregulation of \u201concomirs\u201d miR-21 and miR-155 and downregulation of \u201ctumor suppressor\u201d miR-422a, as well as the reduction of MMR protein and mRNA expression, in NCI and FaDu, compared to controls. Inhibition of miR-21 restored the NNK-induced reduced MSH2 phenotype in both NCI and FaDu, indicating that miR-21 might contribute to MSH2 regulation. Finally, NNK exposure increased NCI and FaDu survival, promoting cancer cell progression. We provide novel findings that deregulated miR-21, miR-155, and miR-422a and MMR gene expression patterns may be valuable biomarkers for lung and head and neck squamous cell cancer progression in smokers.<\/jats:p>","DOI":"10.3390\/cells9041031","type":"journal-article","created":{"date-parts":[[2020,4,22]],"date-time":"2020-04-22T04:15:13Z","timestamp":1587528913000},"page":"1031","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":43,"title":["The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer Cells"],"prefix":"10.3390","volume":"9","author":[{"given":"Sotirios G.","family":"Doukas","sequence":"first","affiliation":[{"name":"Department of Forensic Sciences and Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, Greece"},{"name":"Department of Surgery, The Yale Larynx Laboratory, New Haven, CT 06510, 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":"Department of Surgery, The Yale Larynx Laboratory, New Haven, CT 06510, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George","family":"Lazopoulos","sequence":"additional","affiliation":[{"name":"Department of Cardiothoracic Surgery, Medical School, University of Crete, 71110 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Demetrios A.","family":"Spandidos","sequence":"additional","affiliation":[{"name":"Laboratory of Clinical Virology, Medical School, University of Crete, 71110 Heraklion, Greece"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clarence T.","family":"Sasaki","sequence":"additional","affiliation":[{"name":"Department of Surgery, The Yale Larynx Laboratory, New Haven, CT 06510, USA"}],"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"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"S3","DOI":"10.1016\/j.lungcan.2004.07.998","article-title":"Tobacco smoking and cancer: A brief review of recent epidemiological evidence","volume":"45","author":"Sasco","year":"2004","journal-title":"Lung Cancer"},{"key":"ref_2","unstructured":"Centers for Disease Control and Prevention (US), National Center for Chronic Disease Prevention and Health Promotion (US), and Office on Smoking and Health (US) (2010). 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