Expression and Methylation of Mitochondrial Transcription Factor a in Chronic Obstructive Pulmonary Disease Patients with Lung Cancer

Overview

Journal PLoS One

Specialties General Medicine
Science

Date 2013 Dec 25

PMID 24367550

Citations 17

Authors

Hong Peng

Min Yang

Zhi-Yong Chen

Ping Chen

Cha-Xiang Guan

Xu-Dong Xiang

Shan Cai

Yan Chen

Xiang Fang

Affiliations

Soon will be listed here.

Abstract

Background: Apoptosis plays a central role in the pathogenesis of chronic obstructive pulmonary disease (COPD), and this process can be regulated by mitochondrial transcription factor A (mtTFA). Epigenetics is involved in the regulation and modification of the genes involved in lung cancer and COPD. In this study, we determined the expression of mtTFA and its methylation levels in the COPD patients with lung cancer.

Methods: Twenty-one squamous cell lung cancer patients, 11 with COPD and 10 without COPD, undergoing pneumonectomy were enrolled. The apoptotic index (AI) of pulmonary vascular endothelial cells was analyzed by transferase-mediated deoxyuridine triphosphate-biotin nick end labeling assay. The expression of mtTFA mRNA and protein was measured using PCR, immunohistochemistry and Western-blot. Methylation of the mtTFA promoter was detected using bisulfite sequencing PCR.

Results: Compared to the non-COPD group, the AI was higher, and expression of mtTFA mRNA and protein was lower in the COPD group (P<0.001). Expression of the mtTFA protein was positively correlated with FEV1/Pre (r = 0.892, P<0.001), and negatively correlated with AI (r = -0.749, P<0.001) and smoke index (r = -0.763, P<0.001). Percentage of mtTFA promoter methylation in the COPD patients was significantly higher compared to the non-COPD patients (P<0.05).

Conclusion: These results suggest that the expression of mtTFA mRNA and protein is down-regulated in the lung tissue from the COPD patients with squamous cell lung cancer, and the level of mtTFA protein is related to apoptosis of pulmonary vascular endothelial cells. Aberrant mtTFA methylation may also play an important role in the pathogenesis of COPD.

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References

Barnes P, Shapiro S, Pauwels R . Chronic obstructive pulmonary disease: molecular and cellular mechanisms. Eur Respir J. 2003; 22(4):672-88. DOI: 10.1183/09031936.03.00040703. View

Kasahara Y, Tuder R, Cool C, Lynch D, Flores S, Voelkel N . Endothelial cell death and decreased expression of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in emphysema. Am J Respir Crit Care Med. 2001; 163(3 Pt 1):737-44. DOI: 10.1164/ajrccm.163.3.2002117. View

Liu H, Zhou Y, Boggs S, Belinsky S, Liu J . Cigarette smoke induces demethylation of prometastatic oncogene synuclein-gamma in lung cancer cells by downregulation of DNMT3B. Oncogene. 2007; 26(40):5900-10. DOI: 10.1038/sj.onc.1210400. View

Baryshnikova E, Destro A, Infante M, Cavuto S, Cariboni U, Alloisio M . Molecular alterations in spontaneous sputum of cancer-free heavy smokers: results from a large screening program. Clin Cancer Res. 2008; 14(6):1913-9. DOI: 10.1158/1078-0432.CCR-07-1741. View

Vertino P, Yen R, Gao J, Baylin S . De novo methylation of CpG island sequences in human fibroblasts overexpressing DNA (cytosine-5-)-methyltransferase. Mol Cell Biol. 1996; 16(8):4555-65. PMC: 231454. DOI: 10.1128/MCB.16.8.4555. View

Demedts I, Demoor T, Bracke K, Joos G, Brusselle G . Role of apoptosis in the pathogenesis of COPD and pulmonary emphysema. Respir Res. 2006; 7:53. PMC: 1501017. DOI: 10.1186/1465-9921-7-53. View

Kikuchi S, Yamada D, Fukami T, Maruyama T, Ito A, Asamura H . Hypermethylation of the TSLC1/IGSF4 promoter is associated with tobacco smoking and a poor prognosis in primary nonsmall cell lung carcinoma. Cancer. 2006; 106(8):1751-8. DOI: 10.1002/cncr.21800. View

Wang J, Silva J, Gustafsson C, Rustin P, Larsson N . Increased in vivo apoptosis in cells lacking mitochondrial DNA gene expression. Proc Natl Acad Sci U S A. 2001; 98(7):4038-43. PMC: 31175. DOI: 10.1073/pnas.061038798. View

Chen Y, Hanaoka M, Chen P, Droma Y, Voelkel N, Kubo K . Protective effect of beraprost sodium, a stable prostacyclin analog, in the development of cigarette smoke extract-induced emphysema. Am J Physiol Lung Cell Mol Physiol. 2009; 296(4):L648-56. DOI: 10.1152/ajplung.90270.2008. View

10.

Cai S, Chen P, Zhang C, Chen J, Wu J . Oral N-acetylcysteine attenuates pulmonary emphysema and alveolar septal cell apoptosis in smoking-induced COPD in rats. Respirology. 2009; 14(3):354-9. DOI: 10.1111/j.1440-1843.2009.01511.x. View

11.

Hillemacher T, Frieling H, Moskau S, Muschler M, Semmler A, Kornhuber J . Global DNA methylation is influenced by smoking behaviour. Eur Neuropsychopharmacol. 2008; 18(4):295-8. DOI: 10.1016/j.euroneuro.2007.12.005. View

12.

Egger G, Liang G, Aparicio A, Jones P . Epigenetics in human disease and prospects for epigenetic therapy. Nature. 2004; 429(6990):457-63. DOI: 10.1038/nature02625. View

13.

Xu L, Cai B, Zhu Y . Pathogenesis of cigarette smoke-induced chronic obstructive pulmonary disease and therapeutic effects of glucocorticoids and N-acetylcysteine in rats. Chin Med J (Engl). 2004; 117(11):1611-9. View

14.

Remels A, Schrauwen P, Broekhuizen R, Willems J, Kersten S, Gosker H . Peroxisome proliferator-activated receptor expression is reduced in skeletal muscle in COPD. Eur Respir J. 2007; 30(2):245-52. DOI: 10.1183/09031936.00144106. View

15.

Adcock I, Tsaprouni L, Bhavsar P, Ito K . Epigenetic regulation of airway inflammation. Curr Opin Immunol. 2007; 19(6):694-700. DOI: 10.1016/j.coi.2007.07.016. View

16.

Miyanaga A, Gemma A, Noro R, Kataoka K, Matsuda K, Nara M . Antitumor activity of histone deacetylase inhibitors in non-small cell lung cancer cells: development of a molecular predictive model. Mol Cancer Ther. 2008; 7(7):1923-30. DOI: 10.1158/1535-7163.MCT-07-2140. View

17.

Ikeuchi M, Matsusaka H, Kang D, Matsushima S, Ide T, Kubota T . Overexpression of mitochondrial transcription factor a ameliorates mitochondrial deficiencies and cardiac failure after myocardial infarction. Circulation. 2005; 112(5):683-90. DOI: 10.1161/CIRCULATIONAHA.104.524835. View

18.

Clayton D . Transcription and replication of animal mitochondrial DNAs. Int Rev Cytol. 1992; 141:217-32. DOI: 10.1016/s0074-7696(08)62067-7. View

19.

Shivapurkar N, Stastny V, Suzuki M, Wistuba I, Li L, Zheng Y . Application of a methylation gene panel by quantitative PCR for lung cancers. Cancer Lett. 2006; 247(1):56-71. PMC: 3379713. DOI: 10.1016/j.canlet.2006.03.020. View

20.

Zhang C, Cai S, Chen P, Chen J, Wu J, Wu S . Inhibition of tumor necrosis factor-alpha reduces alveolar septal cell apoptosis in passive smoking rats. Chin Med J (Engl). 2008; 121(7):597-601. View