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. 2016 Apr 5;7(14):18919-26.
doi: 10.18632/oncotarget.7810.

Smoking-promoted oxidative DNA damage response is highly correlated to lung carcinogenesis

Chao Cao  1 , Tianwen Lai  1 , Miao Li  1 , Hongbin Zhou  1 , Dan Lv  1   2 , Zaichun Deng  2 , Songmin Ying  1 , Zhihua Chen  1 , Wen Li  1 , Huahao Shen  1   3
Affiliations

Smoking-promoted oxidative DNA damage response is highly correlated to lung carcinogenesis

Chao Cao et al. Oncotarget. .

Abstract

Oxidative stress induced by tobacco smoking is one of the main causes of DNA damage and is known to be involved in various cancers. Smoking is the leading cause of lung cancer, while the role of cigarette smoke-induced oxidative DNA damage response during lung carcinogenesis is largely unknown. In this study, we investigated oxidative DNA damage response levels in smoking and nonsmoking patients with lung cancer, and evaluated the potential diagnostic value of 8-OHdG for lung cancer. We observed a higher level of 8-OHdG expression and secretion in airways of lung cancer patients than that of noncancer controls. 8-OHdG expression was associated with the TNM stages. Additionally, cigarette smoke-induced oxidative DNA damage response was observed in bronchial epithelial cells in vitro and in vivo. A statistical significance correlation was found between the levels of 8-OHdG and smoking index. With a cut-off value of 2.86 ng/ml, 8-OHdG showed a sensitivity and specificity of 70.0% and 73.7%, respectively, to identify a patient with lung cancer. These findings not only underscore the importance of smoking in oxidative DNA damage response of lung cancer patients, but also suggest 8-OHdG as a potential diagnostic biomarker for lung cancer.

Keywords: 8-OHdG; biomarker; lung cancer; oxidative DNA damage; smoking.

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Conflict of interest statement

CONFLICTS OF INTEREST

The authors declare that they have no conflict of interest.

Figures

Figure 1
Figure 1. Cigarette smoke-induced oxidative DNA damage response in bronchial epithelial cells
A. Representative microphotograph of HBE cells stained with DAPI (blue fluorescence) and anti-8-OHdG antibody (red fluorescence). B. Percentages of 8-OHdG positive cells in control and CSE group were counted (***P < 0.001). C. Oxidative DNA damage response of HBE cells treated with CSE was assessed (FACS, 8-OHdG). D. Significant increased positive of 8-OHdG cells was observed in CSE group than that of controls (P = 0.0195). E. C57BL/6 mice were exposed to smoke for 12 weeks and 24 weeks and oxidative DNA damage response of lung tissues was assessed (IHC, 8-OHdG). F. Percentages of oxidative DNA damage in control and cigarette smoke-exposure group were counted in the lung. Values in the bar graphs are given as mean ± SEM, n=6-8 mice per group; CSE, cigarette smoke extract.
Figure 2
Figure 2. Oxidative DNA damage response in lung cancer patients and noncancer controls
A. Comparison of 8-OHdG levels in BALF between lung cancer and noncancer group. The levels of 8-OHdG were significantly higher in lung cancer patients than those in controls (***P < 0.001). B. Representative examples of immunohistochemistry of 8-OHdG expression in human lung specimens. C. Quantification of 8-OHdG expression in the lung of smokers and nonsmokers (P = 0.0321). D. In subgroup analysis by tumor histology, 8-OHdG expression remained significantly higher in different cell types of lung cancer patients than noncancer controls. E. BALF 8-OHdG concentration were assessed according to TNM stage, and the levels of 8-OHdG was significantly higher in TNM IV stage patients than stage I patients. Horizontal lines in scatter plot represent the mean values. Values in the box plot are given as median (interquartile range); BALF, bronchoalveolar lavage fluid; SCC, squamous cell carcinoma; ADC, adenocarcinoma; SCLC, small-cell lung cancer.
Figure 3
Figure 3. The relationship between smoking and oxidative DNA damage response
A. The levels of 8-OHdG in BALF was significant higher in smokers than nonsmokers both in lung cancer patients (6.8 ± 0.9 ng/ml versus 3.2 ± 0.6 ng/ml, P = 0.0049) and noncancer controls (3.0 ± 0.6 ng/ml versus 1.2 ± 0.2 ng/ml, P = 0.0227). B. Representative examples of immunohistochemistry of 8-OHdG expression in smokers and nonsmokers. C. Quantification of 8-OHdG expression in the lung of smoking and nonsmoking patients with lung cancer (62.7 ± 7.7 % versus 29.8 ± 4.0 %, P = 0.0035) and noncancer controls (38.5 ± 4.1% versus 7.5 ± 2.2 %, P = 0.0004). D. Statistically correlation was observed between levels of 8-OHdG and smoking index (r = 0.5241, P < 0.0001). Values in the bar graphs are given as mean ± SEM; BALF, bronchoalveolar lavage fluid.
Figure 4
Figure 4. Receiver operating characteristic (ROC) curve was performed to evaluate the threshold value of 8-OHdG in differentiating lung cancer from benign diseases
A. With a cut-off value of 2.86 pg/ml, 8-OHdG reached a sensitivity of 70.0%, 95% CI (55.4%, 82.1%), a specificity of 73.7%, 95% CI (56.9%, 86.6%). The area under the curve (AUC) was 0.7363, 95% CI (0.6323, 0.8404). B–C. According to ROC analysis, the cut-off levels of 8-OHdG in BALF for smokers and nonsmokers was 3.23 ng/ml and 1.885 ng/ml, respectively, and the corresponding sensitivity and specificity were 77.4% (95% CI, 58.9%-90.4%) and 60.9% (95% CI, 38.5%-80.3%), 63.2% (95% CI, 38.4%-83.7%) and 80.0% (95% CI, 51.9%-95.7%), respectively. Additionally, AUC for smokers and nonsmokers was 0.7532 (95% CI, 0.6246-0.8817) and 0.7404 (95% CI, 0.5662-0.9145), respectively.
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