Tobacco carcinogen NNK-induced lung cancer animal models and associated carcinogenic mechanisms

Ge, Guangzhe; Xu, Tian‐Rui; Chen, Ceshi

doi:10.1093/abbs/gmv041

Cited by 44 publications

(28 citation statements)

References 143 publications

(122 reference statements)

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“…The control group, which received saline injection, showed no sign of lung tumours ( n = 10). This finding suggested that RBM5 dosage does not affect the initiation of NNK-induced lung cancer and is consistent with previously published data showing that NNK in isolation can induce lung cancer 28 . While not examined at molecular detail here, the histopathological progression of NNK-induced lung cancer progression was consistent with previous publications 28 .…”

Section: Resultssupporting

confidence: 93%

In vivo evidence that RBM5 is a tumour suppressor in the lung

Jamsai

Watkins

O’Connor

et al. 2017

Sci Rep

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Cigarette smoking is undoubtedly a risk factor for lung cancer. Moreover, smokers with genetic mutations on chromosome 3p21.3, a region frequently deleted in cancer and notably in lung cancer, have a dramatically higher risk of aggressive lung cancer. The RNA binding motif 5 (RBM5) is one of the component genes in the 3p21.3 tumour suppressor region. Studies using human cancer specimens and cell lines suggest a role for RBM5 as a tumour suppressor. Here we demonstrate, for the first time, an in vivo role for RBM5 as a tumour suppressor in the mouse lung. We generated Rbm5 loss-of-function mice and exposed them to a tobacco carcinogen NNK. Upon exposure to NNK, Rbm5 loss-of-function mice developed lung cancer at similar rates to wild type mice. As tumourigenesis progressed, however, reduced Rbm5 expression lead to significantly more aggressive lung cancer i.e. increased adenocarcinoma nodule numbers and tumour size. Our data provide in vivo evidence that reduced RBM5 function, as occurs in a large number of patients, coupled with exposure to tobacco carcinogens is a risk factor for an aggressive lung cancer phenotype. These data suggest that RBM5 loss-of-function likely underpins at least part of the pro-tumourigenic consequences of 3p21.3 deletion in humans.

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Section: Resultssupporting

confidence: 93%

In vivo evidence that RBM5 is a tumour suppressor in the lung

Jamsai

Watkins

O’Connor

et al. 2017

Sci Rep

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“…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]. There is evidence that patients with head and neck squamous cell carcinoma often develop primary squamous cell lung carcinoma [65].…”

Section: Discussionmentioning

confidence: 99%

“…NNK is one of the tobacco products that has been evaluated by the International Agency for Research on Cancer (IARC) [73]. Evidence of NNK carcinogenicity was provided by preclinical studies [62]. NNK can be metabolically activated to intermediates that react with DNA forming covalently-bound products known as adducts.…”

Section: Discussionmentioning

confidence: 99%

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

Doukas

Vageli²,

Lazopoulos

et al. 2020

Cells

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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.Cells 2020, 9, 1031 2 of 22 and neck squamous cell carcinoma (HNSCC), represents one of the most aggressive malignancies with a high rate of mortality. [8,9]. 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]. It is known that tobacco smoke contains a mixture of thousands of compounds, including a large number of known carcinogens [2]. It is believed that exposure of cells to tobacco smoke carcinogens can lead to DNA damage, which may cause chromosomal instability and increased cell proliferation [10][11][12][13]. In particular, 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 also been shown to upregulate oncogenic pathways [15][16][17].The development and progression of lung and head and neck malignancies appear to be a complex process. Although multiple diagnostic and prognostic markers have been identified for both lung and head and neck cancers [18,19], the precise molecular mechanisms involved in the development and progression of these malignancies remain unclear.We understand that a functional DNA repair mechanism that includes the recognition and repair of mismatch DNA errors during DNA replication is essential in eliminating the harmful effect of several environmental risk factors, such as NNK, on the exposed cells [20][21][22][23]. A number of studies have shown that reduced expression of mismatch DNA repair (MMR) genes increases the incidence of microsatellite ...

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“…We hypothesized that NNK serves as a tumor initiator and Nic works as a tumor promotion factor to induce breast carcinogenesis in vitro. Several studies have described the proposed role of NNK in tumor initiation . We provide considerable evidence that even very low combined doses of carcinogens, 1pM of Nic and 100 femtM of NNK have a more potent effect on the non‐tumorigenic breast cells during long‐time exposure than their individual doses.…”

Section: Discussionmentioning

confidence: 99%

Long‐term exposure to extremely low‐dose of nicotine and 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) induce non‐malignant breast epithelial cell transformation through activation of the a9‐nicotinic acetylcholine receptor‐mediated signaling pathway

Fararjeh

Chen

et al. 2018

Environmental Toxicology

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Breast cancer (BC) is the most common cancer affecting women worldwide and has been associated with active tobacco smoking. Low levels of nicotine (Nic) and 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK), have been detected in cases of second‐hand smoke (SHS). However, the correlation between SHS and BC risk remains controversial. In this study, we investigated whether the physiological SHS achievable dose of Nic and tobacco specific nitrosamine, NNK act together to induce breast carcinogenesis using an in vitro breast cell carcinogenesis model. Immortalized non‐tumorigenic breast epithelial cell line, HBL‐100 used for a time‐course assay, was exposed to very low levels of either Nic or NNK, or both. The time‐course assay consisted of 23 cycles of nitrosamines treatment. In each cycle, HBL‐100 cells were exposed to 1pM of Nic and/or 100 femtM of NNK for 48 hours. Cells were passaged every 3 days and harvested after 10, 15, and 23 cycles. Our results demonstrated that the tumorigenicity of HBL‐100, defined by soft agar colony forming, proliferation, migration and invasion abilities, was enhanced by co‐exposure to physiologically SHS achievable doses of Nic and NNK. In addition, α9‐nAChR signaling activation, which plays an important role in cellular proliferation and cell survival, was also observed. Importantly, an increase in stemness properties including the prevalence of CD44+/CD24− cells, increase Nanog expression and mammosphere‐forming ability were also observed. Our results indicate that chronic and long term exposure to environmental tobacco smoke, may induce breast cell carcinogenesis even at extremely low doses.

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Tobacco carcinogen NNK-induced lung cancer animal models and associated carcinogenic mechanisms

Cited by 44 publications

References 143 publications

In vivo evidence that RBM5 is a tumour suppressor in the lung

In vivo evidence that RBM5 is a tumour suppressor in the lung

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

Long‐term exposure to extremely low‐dose of nicotine and 4‐(methylnitrosamino)‐1‐(3‐pyridyl)‐1‐butanone (NNK) induce non‐malignant breast epithelial cell transformation through activation of the a9‐nicotinic acetylcholine receptor‐mediated signaling pathway

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