Lung carcinogenesis by tobacco smoke

ArticleinInternational Journal of Cancer 131(12):2724-32 · December 2012with24 Reads
DOI: 10.1002/ijc.27816 · Source: PubMed
Abstract
Cigarette smoke is a complex mixture of chemicals including multiple genotoxic lung carcinogens. The classic mechanisms of carcinogen metabolic activation to DNA adducts, leading to miscoding and mutations in critical growth control genes, applies to this mixture but some aspects are difficult to establish because of the complexity of the exposure. This article discusses certain features of this mechanism including the role of nicotine and its receptors; lung carcinogens, co-carcinogens and related substances in cigarette smoke; structurally characterized DNA adducts in the lungs of smokers; the mutational consequences of DNA adduct formation in smokers' lungs; and biomarkers of nicotine and carcinogen uptake as related to lung cancer. While there are still uncertainties which may never be fully resolved, the general mechanisms by which cigarette smoking causes lung cancer are well understood and provide insights relevant to prevention of lung cancer, the number one cancer killer in the world, causing 1.37 million deaths per year.
    • "NSCLC oncogenesis is a multistep process, and includes genetic mutations and epigenetic changes, among others. Environmental factors, such as the smoking and drinking habits of the patients, and air pollution, also play a major role in lung cancer progression (Hecht, 2012; Dresler, 2013). So far, the molecular mechanism regulating the development and progression of NSCLC remains unclear. "
    [Show abstract] [Hide abstract] ABSTRACT: Abnormal expression of microRNA-135a (miR-135a) is closely associated with oncogenesis. However, the relationship between serum miR-135a levels and the clinical parameters and prognosis of non-small cell lung cancer (NSCLC) remain unclear. The study aimed to investigate the clinical significance of serum miR-135a expression in patients with NSCLC. miR-135a expression was analyzed by real-time PCR and its correlation with NSCLC was determined by various statistical methods for 104 NSCLC patients and 40 healthy volunteers. The serum miR-135a level was significantly lower in NSCLC patients than in healthy control subjects (P < 0.01), and was closely related to distant metastasis (P < 0.015), lymphatic metastasis (P = 0.000), TNM (tumor node metastasis) stage (P = 0.001), and pathological stage (P = 0.021) of NSCLC. The five year overall survival was significantly lower in patients with low miR-135a expression than that in patients with high serum miR-135a levels (P = 0.010). Multivariate analysis showed that serum miR-135a level could be treated as an independent risk factor for NSCLC prognosis (P = 0.011). In conclusion, the serum miR-135a level was downregulated in NSCLC patients, and was associated with poor prognosis. Additionally, it can be used as a biomarker for NSCLC prognosis.
    Article · Aug 2016
    • "Different classes of chemical carcinogens are present in tobacco smoke including the polycyclic aromatic hydrocarbons (PAHs) such as benzo[a]pyrene (B[a]P), dibenz[a,h]anthracene and dibenzo[a,l] pyrene. The DNA-reactive metabolites of PAHs are considered to be among the primary tobacco smoke carcinogens [7, 12] . Metabolic activation of these and other chemical compounds found in tobacco smoke can generate intermediates that react with DNA bases and produce DNA adducts. "
    [Show abstract] [Hide abstract] ABSTRACT: Exposure to tobacco smoke is the number one risk factor for lung cancer. Although the DNA damaging properties of tobacco smoke have been well documented, relatively few studies have examined its effect on DNA repair pathways. This is especially true for the nucleotide excision repair (NER) pathway which recognizes and removes many structurally diverse DNA lesions, including those introduced by chemical carcinogens present in tobacco smoke. The aim of the present study was to investigate the effect of tobacco smoke on NER in human lung cells. We studied the effect of cigarette smoke condensate (CSC), a surrogate for tobacco smoke, on the NER pathway in two different human lung cell lines; IMR-90 lung fibroblasts and BEAS-2B bronchial epithelial cells. To measure NER, we employed a slot-blot assay to quantify the introduction and removal of UV light-induced 6-4 photoproducts and cyclobutane pyrimidine dimers. We find a dose-dependent inhibition of 6-4 photoproduct repair in both cell lines treated with CSC. Additionally, the impact of CSC on the abundance of various NER proteins and their respective RNAs was investigated. The abundance of XPC protein, which is required for functional NER, is significantly reduced by treatment with CSC while the abundance of XPA protein, also required for NER, is unaffected. Both XPC and XPA RNA levels are modestly reduced by CSC treatment. Finally, treatment of cells with MG-132 abrogates the reduction in the abundance of XPC protein produced by treatment with CSC, suggesting that CSC enhances proteasome-dependent turnover of the protein that is mediated by ubiquitination. Together, these findings indicate that tobacco smoke can inhibit the same DNA repair pathway that is also essential for the removal of some of the carcinogenic DNA damage introduced by smoke itself, increasing the DNA damage burden of cells exposed to tobacco smoke.
    Full-text · Article · Jul 2016
    • "The identification of the population with a higher risk of lung cancer from the residents of air polluted regions and the 1.4 billion worldwide smokers is critical for lung cancer prevention and treatment outcome. The metabolites of nicotine, NNK, and PAHs are related to lung cancer [3], and a chemokine CCL20 may also be associated with lung cancer risk in smokers [46]. However, a precise prediction approach remains an urgent need to identify those populations. "
    [Show abstract] [Hide abstract] ABSTRACT: Indoor and outdoor air pollution has been classified as group I carcinogen in humans, but the underlying tumorigenesis remains unclear. Here, we screened for abnormal long noncoding RNAs (lncRNAs) in lung cancers from patients living in Xuanwei city which has the highest lung cancer incidence in China due to smoky coal combustion-generated air pollution. We reported that Xuanwei patients had much more dysregulated lncRNAs than patients from control regions where smoky coal was not used. The lncRNA CAR intergenic 10 (CAR10) was up-regulated in 39/62 (62.9%) of the Xuanwei patients, which was much higher than in patients from control regions (32/86, 37.2%; p=0.002). A multivariate regression analysis showed an association between CAR10 overexpression and air pollution, and a smoky coal combustion-generated carcinogen dibenz[a,h]anthracene up-regulated CAR10 by increasing transcription factor FoxF2 expression. CAR10 bound and stabilized transcription factor Y-box-binding protein 1 (YB-1), leading to up-regulation of the epidermal growth factor receptor (EGFR) and proliferation of lung cancer cells. Knockdown of CAR10 inhibited cell growth in vitro and tumor growth in vivo. These results demonstrate the role of lncRNAs in environmental lung carcinogenesis, and CAR10-YB-1 represents a potential therapeutic target.
    Article · Jun 2016
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