Dysregulation of microRNAs (miRNAs), particularly their downregulation, has been widely shown to be associated with the development of lung cancer. Downregulation of miRNAs leads to the overactivation of their oncogene targets, while upregulation of some miRNAs leads to inhibition of important tumor suppressors. Research has implicated cigarette smoke in miRNA dysregulation, leading to carcinogenesis. Cigarette smoke may lead to genetic or epigenetic damage to miRNAs, many of which map to fragile sites and some of which contain single nucleotide polymorphisms. Cigarette smoke may also cause dysregulation by affecting regulatory mechanisms controlling miRNA expression. Researchers have shown a correlation between smoke-exposure-induced dysregulation of miRNAs and age. Furthermore, dysregulation seems to be associated with intensity and duration of smoke exposure and duration of cessation. Longer exposure at a threshold level is needed for irreversibility of changes in expression. Better understanding of miRNA dysregulation may allow for improved biomonitoring and treatment regimens for lung cancer. 1. Introduction In the United States, lung cancer is the second most common cancer to occur in men and women [1], yet with a five-year survival rate of only 15%, lung cancer represents the leading cause of cancer-related deaths [1, 2]. This poor survival is largely a product of lack of early screenable biomarkers, which leads to detection of the cancer at an advanced and typically untreatable stage [2]. Furthermore, histologic classification of lung cancer is limited, given the genotypic heterogeneity among cells of a similar type [3]. Such heterogeneity causes varied responses to treatment and limits the efficacy of a single or generalized therapy. Previous research has analyzed gene expression signatures to elucidate the heterogeneity of lung cancers, allowing for more accurate diagnosis and prognosis and permitting creation of more targeted therapies [3, 4]. Nevertheless, as mRNAs may be regulated posttranscriptionally, only determining mRNA expression may not fully portray the biological mechanisms involved in cancer initiation and progression [2]. Computer models have predicted that miRNAs, which posttranscriptionally suppresses translation of mRNA, accounts for 1/3 of total regulation of the genome [5]. Dysregulation of miRNA, thus, can have an important consequence in the dysregulation of genes, and miRNA analysis can provide a more comprehensive understanding of lung cancer pathogenesis. Moreover, research has found that exposure to cigarette smoke can
References
[1]
A. Jemal, R. Siegel, J. Xu, and E. Ward, “Cancer statistics, 2010,” CA Cancer Journal for Clinicians, vol. 60, no. 5, pp. 277–300, 2010.
[2]
X. Wu, M. G. Piper-Hunter, M. Crawford et al., “MicroRNAs in the pathogenesis of lung cancer,” Journal of Thoracic Oncology, vol. 4, no. 8, pp. 1028–1034, 2009.
[3]
K. Shedden, J. M. G. Taylor, S. A. Enkemann et al., “Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study,” Nature Medicine, vol. 14, no. 8, pp. 822–827, 2008.
[4]
M. Meyerson and D. Carbone, “Genomic and proteomic profiling of lung cancers: lung cancer classification in the age of targeted therapy,” Journal of Clinical Oncology, vol. 23, no. 14, pp. 3219–3226, 2005.
[5]
C. Z. Chen, “MicroRNAs as oncogenes and tumor suppressors,” The New England Journal of Medicine, vol. 353, no. 17, pp. 1768–1771, 2005.
[6]
G. R. Pottelberge, P. Mestdagh, K. R. Bracke et al., “MicroRNA expression in induced sputum of smokers and patients with chronic obstructive pulmonary disease,” The American Journal of Respiratory and Critical Care Medicine, vol. 183, no. 7, pp. 898–906, 2010.
[7]
A. Esquela-Kerscher and F. J. Slack, “Oncomirs: microRNAs with a role in cancer,” Nature Reviews Cancer, vol. 6, no. 4, pp. 259–269, 2006.
[8]
A. Izzotti, G. A. Calin, P. Arrigo, V. E. Steele, C. M. Croce, and S. De Flora, “Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke,” FASEB Journal, vol. 23, no. 3, pp. 806–812, 2009.
[9]
F. Schembri, S. Sridhar, C. Perdomo et al., “MicroRNAs as modulators of smoking-induced gene expression changes in human airway epithelium,” Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 7, pp. 2319–2324, 2009.
[10]
G. A. Calin and C. M. Croce, “MicroRNA signatures in human cancers,” Nature Reviews Cancer, vol. 6, no. 11, pp. 857–866, 2006.
[11]
D. F. Church and W. A. Pryor, “Free-radical chemistry of cigarette smoke and its toxicological implications,” Environmental Health Perspectives, vol. 64, pp. 111–126, 1985.
[12]
A. Valavanidis, T. Vlachogianni, and K. Fiotakis, “Tobacco smoke: involvement of reactive oxygen species and stable free radicals in mechanisms of oxidative damage, carcinogenesis and synergistic effects with other respirable particles,” International Journal of Environmental Research and Public Health, vol. 6, no. 2, pp. 445–462, 2009.
[13]
G. A. Calin, C. Sevignani, C. D. Dumitru et al., “Human microRNA genes are frequently located at fragile sites and genomic regions involved in cancers,” Proceedings of the National Academy of Sciences of the United States of America, vol. 101, no. 9, pp. 2999–3004, 2004.
[14]
A. Izzotti, P. Larghero, R. Balansky, U. Pfeffer, V. E. Steele, and S. De Flora, “Interplay between histopathological alterations, cigarette smoke and chemopreventive agents in defining microRNA profiles in mouse lung,” Mutation Research, vol. 717, no. 1-2, pp. 17–24, 2011.
[15]
N. Fujimoto, M. Wislez, J. Zhang et al., “High expression of ErbB family members and their ligands in lung adenocarcinomas that are sensitive to inhibition of epidermal growth factor receptor,” Cancer Research, vol. 65, no. 24, pp. 11478–11485, 2005.
[16]
R. Duan, C. H. Pak, and P. Jin, “Single nucleotide polymorphism associated with mature miR-125a alters the processing of pri-miRNA,” Human Molecular Genetics, vol. 16, no. 9, pp. 1124–1131, 2007.
[17]
L. He, X. He, L. P. Lim et al., “A microRNA component of the p53 tumour suppressor network,” Nature, vol. 447, no. 7148, pp. 1130–1134, 2007.
[18]
S. A. Ahrendt, J. T. Chow, S. C. Yang et al., “Alcohol consumption and cigarette smoking increase the frequency of p53 mutations in non-small cell lung cancer,” Cancer Research, vol. 60, no. 12, pp. 3155–3159, 2000.
[19]
K. Kondo, H. Tsuzuki, M. Sasa, M. Sumitomo, T. Uyama, and Y. Monden, “A dose-response relationship between the frequency of p53 mutations and tobacco consumption in lung cancer patients,” Journal of Surgical Oncology, vol. 61, no. 1, pp. 20–26, 1996.
[20]
I. Chiba, T. Takahashi, and M.M. Nau, “Mutations in the P53 gene are frequent in primary, resected non-small cell lung cancer Chiba I, Takahashi T, Nau MM Et Al. NCI-Navy Medical Oncology Branch, National Cancer Institute, National Naval Medical Center, Bethesda, MD 20814. Oncogene 1990;5:1603–1610,” Lung Cancer, vol. 7, no. 4, p. 265, 1991.
[21]
P. Hainaut and G. P. Pfeifer, “Patterns of p53→T transversions in lung cancers reflect the primary mutagenic signature of DNA-damage by tobacco smoke,” Carcinogenesis, vol. 22, no. 3, pp. 367–374, 2001.
[22]
L. He, X. He, S. W. Lowe, and G. J. Hannon, “microRNAs join the p53 network: another piece in the tumour-suppression puzzle,” Nature Reviews Cancer, vol. 7, no. 11, pp. 819–822, 2007.
[23]
N. Raver-Shapira, E. Marciano, E. Meiri et al., “Transcriptional activation of miR-34a contributes to p53-mediated apoptosis,” Molecular Cell, vol. 26, no. 5, pp. 731–743, 2007.
[24]
S. Roush and F. J. Slack, “The let-7 family of microRNAs,” Trends in Cell Biology, vol. 18, no. 10, pp. 505–516, 2008.
[25]
S. M. Johnson, H. Grosshans, J. Shingara et al., “RAS is regulated by the let-7 microRNA family,” Cell, vol. 120, no. 5, pp. 635–647, 2005.
[26]
A. A. Russo, L. Tong, J. O. Lee, P. D. Jeffrey, and N. P. Pavletich, “Structural basis for inhibition of the cyclin-dependent kinase Cdk6 by the tumour suppressor p16(INK4a),” Nature, vol. 395, no. 6699, pp. 237–243, 1998.
[27]
C. D. Johnson, A. Esquela-Kerscher, G. Stefani et al., “The let-7 microRNA represses cell proliferation pathways in human cells,” Cancer Research, vol. 67, no. 16, pp. 7713–7722, 2007.
[28]
F. J. Slack and J. B. Weidhass, “MicroRNAs as a potential magic bullet in cancer,” Future Oncology, vol. 2, no. 1, pp. 73–82, 2006.
[29]
R. Yao, Y. Wang, F. D'Agostini et al., “K-ras mutations in lung tumors from p53 mutant mice exposed to cigarette smoke,” Experimental Lung Research, vol. 31, no. 2, pp. 271–281, 2005.
[30]
A. Izzotti, M. Bagnasco, C. Cartiglia et al., “Chemoprevention of genome, transcriptome, and proteome alterations induced by cigarette smoke in rat lung,” European Journal of Cancer, vol. 41, no. 13, pp. 1864–1874, 2005.
[31]
A. Izzotti, G. A. Calin, V. E. Steele, C. M. Croce, and S. De Flora, “Relationships of microRNA expression in mouse lung with age and exposure to cigarette smoke and light,” FASEB Journal, vol. 23, no. 9, pp. 3243–3250, 2009.
[32]
A. Izzotti, R. M. Balansky, A. Camoirano et al., “Birth-related genomic and transcriptional changes in mouse lung: modulation by transplacental N-acetylcysteine,” Mutation Research—Reviews in Mutation Research, vol. 544, no. 2-3, pp. 441–449, 2003.
[33]
R. Balansky, G. Ganchev, M. Iltcheva, V. E. Steele, F. D'Agostini, and S. De Flora, “Potent carcinogenicity of cigarette smoke in mice exposed early in life,” Carcinogenesis, vol. 28, no. 10, pp. 2236–2243, 2007.
[34]
M. Yee, P. F. Vitiello, J. M. Roper et al., “Type II epithelial cells are critical target for hyperoxia-mediated impairment of postnatal lung development,” The American Journal of Physiology—Lung Cellular and Molecular Physiology, vol. 291, no. 5, pp. L1101–L1111, 2006.
[35]
S. De Flora, S. Scarfì, A. Izzotti et al., “Induction by 7,12-dimethylbenz(a)anthracene of molecular and biochemical alterations in transformed human mammary epithelial stem cells, and protection by N-acetylcysteine,” International Journal of Oncology, vol. 29, no. 3, pp. 521–529, 2006.
[36]
A. Izzotti, P. Larghero, M. Longobardi et al., “Dose-responsiveness and Persistence of MicroRNA Expression Alterations Induced by Cigarette Smoke in Mouse Lung,” Mutation Research, vol. 717, no. 1-2, pp. 9–16, 2011.
[37]
A. Izzotti, R. M. Balansky, C. Cartiglia, A. Camoirano, M. Longobardi, and S. De Flora, “Genomic and transcriptional alterations in mouse fetus liver after transplacental exposure to cigarette smoke,” FASEB Journal, vol. 17, no. 9, pp. 1127–1129, 2003.
[38]
A. Izzotti, C. Cartiglia, M. Longobardi et al., “Alterations of gene expression in skin and lung of mice exposed to light and cigarette smoke,” FASEB Journal, vol. 18, no. 13, pp. 1559–1561, 2004.
[39]
S. Deflora, F. Dagostini, R. Balansky et al., “High susceptibility of neonatal mice to molecular, biochemical and cytogenetic alterations induced by environmental cigarette smoke and light,” Mutation Research—Reviews in Mutation Research, vol. 659, no. 1-2, pp. 137–146, 2008.
[40]
IARC Monographs on the Evaluation of Carcinogenic Risks to Humans: Tobacco Smoke and Involuntary Smoking, vol. 84, International Agency for Research on Cancer. World Health Organization, 2004.
[41]
J. Lu, G. Getz, E. A. Miska et al., “MicroRNA expression profiles classify human cancers,” Nature, vol. 435, no. 7043, pp. 834–838, 2005.
[42]
A. Izzotti, G. A. Calin, V. E. Steele et al., “Chemoprevention of cigarette smoke-induced alterations of microRNA expression in rat lungs,” Cancer Prevention Research, vol. 3, no. 1, pp. 62–72, 2010.
[43]
J. Krutzfeldt, N. Rajewsky, R. Braich et al., “Silencing of microRNAs in vivo with ‘antagomirs’,” Nature, vol. 438, no. 7068, pp. 685–689, 2005.
[44]
G. Meister, M. Landthaler, Y. Dorsett, and T. Tuschl, “Sequence-specific inhibition of microRNA-and siRNA-induced RNA silencing,” RNA, vol. 10, no. 3, pp. 544–550, 2004.
[45]
N. E. Kohl, S. D. Mosser, S. J. DeSolms et al., “Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor,” Science, vol. 260, no. 5116, pp. 1934–1937, 1993.
[46]
C. Arteaga, “Targeting HER1/EGFR: a molecular approach to cancer therapy,” Seminars in Oncology, vol. 30, no. 3, pp. 3–14, 2003.
[47]
B. E. Johnson and J. V. Heymach, “Farnesyl transferase inhibitors for patients with lung cancer,” Clinical Cancer Research, vol. 10, no. 12, pp. 4254S–4257S, 2004.
