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
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 progno...
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| Format: | Article |
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MDPI AG
2020-04-01
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| Series: | Cells |
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| Online Access: | https://www.mdpi.com/2073-4409/9/4/1031 |
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| author | Sotirios G. Doukas Dimitra P. Vageli George Lazopoulos Demetrios A. Spandidos Clarence T. Sasaki Aristidis Tsatsakis |
| author_facet | Sotirios G. Doukas Dimitra P. Vageli George Lazopoulos Demetrios A. Spandidos Clarence T. Sasaki Aristidis Tsatsakis |
| author_sort | Sotirios G. Doukas |
| collection | DOAJ |
| description | 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 μM) or high (2 μM) dose of NNK induced significant upregulation of “oncomirs” miR-21 and miR-155 and downregulation of “tumor suppressor” 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. |
| first_indexed | 2024-03-10T20:19:11Z |
| format | Article |
| id | doaj.art-4c0d48666f38467590705e97d8b3e1ef |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-10T20:19:11Z |
| publishDate | 2020-04-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cells |
| spelling | doaj.art-4c0d48666f38467590705e97d8b3e1ef2023-11-19T22:19:02ZengMDPI AGCells2073-44092020-04-0194103110.3390/cells9041031The Effect of NNK, A Tobacco Smoke Carcinogen, on the miRNA and Mismatch DNA Repair Expression Profiles in Lung and Head and Neck Squamous Cancer CellsSotirios G. Doukas0Dimitra P. Vageli1George Lazopoulos2Demetrios A. Spandidos3Clarence T. Sasaki4Aristidis Tsatsakis5Department of Forensic Sciences and Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, GreeceDepartment of Surgery, The Yale Larynx Laboratory, New Haven, CT 06510, USADepartment of Cardiothoracic Surgery, Medical School, University of Crete, 71110 Heraklion, GreeceLaboratory of Clinical Virology, Medical School, University of Crete, 71110 Heraklion, GreeceDepartment of Surgery, The Yale Larynx Laboratory, New Haven, CT 06510, USADepartment of Forensic Sciences and Laboratory of Toxicology, Medical School, University of Crete, 71003 Heraklion, GreeceTobacco 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 μM) or high (2 μM) dose of NNK induced significant upregulation of “oncomirs” miR-21 and miR-155 and downregulation of “tumor suppressor” 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.https://www.mdpi.com/2073-4409/9/4/1031tobacco smokeNNKhead and neck cancerlung cancerMismatch DNA repairMSH2 |
| spellingShingle | Sotirios G. Doukas Dimitra P. Vageli George Lazopoulos Demetrios A. Spandidos Clarence T. Sasaki Aristidis Tsatsakis 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 Cells tobacco smoke NNK head and neck cancer lung cancer Mismatch DNA repair MSH2 |
| 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | tobacco smoke NNK head and neck cancer lung cancer Mismatch DNA repair MSH2 |
| url | https://www.mdpi.com/2073-4409/9/4/1031 |
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