Abstract
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.
Highlights
Plenty of epidemiologic data have shown the association of tobacco smoking with the development of human malignancies [1,2]
Respectively, versus untreated controls. (Data were obtained from three independent experiments). We found that both NCI and FaDu exposed to 2 μM of NNK produced significantly. We found that both NCI and FaDu exposed to 2 μM of NNK produced significantly lower transcriptional levels of hMSH2 and hMLH1 compared to those exposed to 1 μM
We demonstrate that tobacco smoke carcinogen, NNK, can affect the expression of cancer-related miR-21, miR-155 and miR-422a, which have a regulatory role in the Mismatch DNA repair (MMR) mechanism, causing downregulation of Tobacco smoke is an established risk factor of lung and head and neck cancers [61,62], and is considered to contribute to their recurrence and progression [63,64]
Summary
Plenty of epidemiologic data have shown the association of tobacco smoking with the development of human malignancies [1,2]. Lung cancer has the highest mortality rates in the world for both men and women, and is the most common type of malignancy in men [7]. Cells 2020, 9, 1031 and neck squamous cell carcinoma (HNSCC), represents one of the most aggressive malignancies with a high rate of mortality. Tobacco smoking has been one of the most well-established risk factors for both lung and head and neck cancers [1,2,3,4,5,6,7,8]. Tobacco-specific nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), which is one of the chemicals in tobacco smoke, has been linked to lung and head and neck cancer [14], and has been shown to upregulate oncogenic pathways [15,16,17]
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