Lung cancers account for a huge percentage of death in industrialized countries, and hence there is an increasing call for the development of novel treatments. These malignancies are caused by a combination of environmental factors, principally cigarette smoking and genetic alterations. MicroRNAs (miRNAs) are a recently discovered class of regulatory noncoding small RNAs with a significance in numerous biological processes. Strong evidence links miRNA impaired expression profiles and pathways to the etiology of several diseases, including neoplasia. This paper focuses on the emerging role of miRNA function in lung cancer development with particular highlighting on the use of miRNA profiles and polymorphisms for the molecular and biological characterization of tumor pulmonary growth and progression. Furthermore, we underline the potential utility of lung cancer-associated miRNAs as clinical biomarkers with a diagnostic, prognostic, and therapeutic significance and give emphasis to the promising novel miRNA-based curative strategies. 1. Introduction Lung cancer is one of the commonest neoplasia and the first cause of death worldwide, in both women and men, with an increasing incidence rate. Less than 10% of people with the disease live longer than five years after diagnosis [1, 2]. Lung tumor is characterized by a preponderance of carcinoma derived from changes and abnormally growth of epithelial lung cells. Small cell lung carcinoma (SCLC) and non-small cell lung carcinoma (NSCLC) are two main distinct types of this neoplasia that have considerable differences in pathogenetic mechanisms, cellular origin, molecular changes and histopathological and clinical features [1]. Furthermore, they show a different response to therapeutic treatments such as surgical resection, radiation, and chemotherapy. NSCLC comprises approximately 80% of all lung cancers and can be classified into adenocarcinoma (AC), squamous cell carcinoma (SqCC), and large cell carcinoma, whereas SCLC tends to spread more quickly than NSCLC and can be divided into small cell carcinoma (SCC), mixed small cell/large cell carcinoma, and combined small cell carcinoma. Symptoms can be absent or very moderate, mainly in the early stages of tumor transformation, so that a large percentage of patients is diagnosed only in advanced stage of tumor extension with a consequent poor treatment outcome. Although surgery provides a potential curative strategy, patients often develop recurrence with a survival rate that remains very low especially in subjects with metastatic disease. Therefore, looking for
References
[1]
P. C. Hoffman, A. M. Mauer, and E. E. Vokes, “Lung cancer,” Lancet, vol. 355, no. 9202, pp. 479–485, 2000.
[2]
A. Jemal, R. Siegel, E. Ward, T. Murray, J. Xu, and M. J. Thun, “Cancer statistics, 2007,” CA: A Cancer Journal for Clinicians, vol. 57, no. 1, pp. 43–66, 2007.
[3]
R. Sangha, J. Price, and C. A. Butts, “Adjuvant therapy in non-small cell lung cancer: current and future directions,” Oncologist, vol. 15, no. 8, pp. 862–872, 2010.
[4]
P. P. Massion and D. P. Carbone, “The molecular basis of lung cancer: molecular abnormalities and therapeutic implications,” Respiratory Research, vol. 41, no. 1, pp. 12–26, 2003.
[5]
J. Clavel, “Progress in the epidemiological understanding of gene-environment interactions in major diseases: cancer,” Comptes Rendus Biologies, vol. 330, no. 4, pp. 306–317, 2007.
[6]
D. P. Bartel, “MicroRNAs: genomics, biogenesis, mechanism, and function,” Cell, vol. 116, no. 2, pp. 281–297, 2004.
[7]
M. A. Valencia-Sanchez, J. Liu, G. J. Hannon, and R. Parker, “Control of translation and mRNA degradation by miRNAs and siRNAs,” Genes and Development, vol. 20, no. 5, pp. 515–524, 2006.
[8]
A. M. Denli, B. B. Tops, R. H. Plasterk, R. F. Ketting, and G. J. Hannon, “Processing of primary microRNAs by the Microprocessor complex,” Nature, vol. 432, no. 7014, pp. 231–235, 2004.
[9]
V. N. Kim, “MicroRNA biogenesis: coordinated cropping and dicing,” Nature Reviews Molecular Cell Biology, vol. 6, no. 5, pp. 376–385, 2005.
[10]
S. Griffiths-Jones, H. K. Saini, S. van Dongen, and A. J. Enright, “miRBase: tools for microRNA genomics,” Nucleic Acids Research, vol. 36, supplement 1, pp. D154–D158, 2008.
[11]
M. Yoda, T. Kawamata, Z. Paroo et al., “ATP-dependent human RISC assembly pathways,” Nature Structural & Molecular Biology, vol. 17, no. 1, pp. 17–23, 2010.
[12]
E. Berezikov, V. Guryev, J. van de Belt, E. Wienholds, R. H. A. Plasterk, and E. Cuppen, “Phylogenetic shadowing and computational identification of human microRNA genes,” Cell, vol. 120, no. 1, pp. 21–24, 2005.
[13]
G. J. Weiss, L. T. Bemis, E. Nakajima et al., “EGFR regulation by microRNA in lung cancer: correlation with clinical response and survival to gefitinib and EGFR expression in cell lines,” Annals of Oncology, vol. 19, no. 6, pp. 1053–1059, 2008.
[14]
A. G. Bader, D. Brown, and M. Winkler, “The promise of microRNA replacement therapy,” Cancer Research, vol. 70, no. 18, pp. 7027–7030, 2010.
[15]
J. A. Bishop, H. Benjamin, H. Cholakh, A. Chajut, D. P. Clark, and W. H. Westra, “Accurate classification of non-small cell lung carcinoma using a novel microRNA-based approach,” Clinical Cancer Research, vol. 16, no. 2, pp. 610–619, 2010.
[16]
R. Hummel, D. J. Hussey, and J. Haier, “MicroRNAs: predictors and modifiers of chemo- and radiotherapy in different tumour types,” European Journal of Cancer, vol. 46, no. 2, pp. 298–311, 2010.
[17]
P. J. Mishra and J. R. Bertino, “MicroRNA polymorphisms: the future of pharmacogenomics, molecular epidemiology and individualized medicine,” Pharmacogenomics, vol. 10, no. 3, pp. 399–416, 2009.
[18]
B. Zhang, X. Pan, G. P. Cobb, and T. A. Anderson, “MicroRNAs as oncogenes and tumor suppressors,” Developmental Biology, vol. 302, no. 1, pp. 1–12, 2007.
[19]
N. Yanaihara, N. Caplen, E. Bowman et al., “Unique microRNA molecular profiles in lung cancer diagnosis and prognosis,” Cancer Cell, vol. 9, no. 3, pp. 189–198, 2006.
[20]
H. Osada and T. Takahashi, “let-7 and miR-17-92: small-sized major players in lung cancer development,” Cancer Science, vol. 102, no. 1, pp. 9–17, 2011.
[21]
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.
[22]
J. Takamizawa, H. Konishi, K. Yanagisawa et al., “Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival,” Cancer Research, vol. 64, no. 11, pp. 3753–3756, 2004.
[23]
Y. S. Lee and A. Dutta, “The tumor suppressor microRNA let-7 represses the HMGA2 oncogene,” Genes and Development, vol. 21, no. 9, pp. 1025–1030, 2007.
[24]
M. S. Kumar, S. J. Erkeland, R. E. Pester et al., “Suppression of non-small cell lung tumor development by the let-7 microRNA family,” Proceedings of the National Academy of Sciences of the United States of America, vol. 105, no. 10, pp. 3903–3908, 2008.
[25]
B. Liu, X. C. Peng, X. L. Zheng, J. Wang, and Y. W. Qin, “MiR-126 restoration down-regulate VEGF and inhibit the growth of lung cancer cell lines in vitro and in vivo,” Lung Cancer, vol. 66, no. 2, pp. 169–175, 2009.
[26]
Z. Chen, H. Zeng, Y. Guo et al., “miRNA-145 inhibits non-small cell lung cancer cell proliferation by targeting c-Myc,” Journal of Experimental & Clinical Cancer Research, vol. 29, no. 1, pp. 151–160, 2010.
[27]
W. Cho, A. Chow, and J. Au, “MiR-145 inhibits cell proliferation of human lung adenocarcinoma by targeting EGFR and NUDT1,” RNA Biology, vol. 8, no. 1, pp. 125–131, 2011.
[28]
R. Wang, Z. X. Wang, J. S. Yang, X. Pan, W. De, and L. B. Chen, “MicroRNA-451 functions as a tumor suppressor in human non-small cell lung cancer by targeting ras-related protein 14 (RAB14),” Oncogene, vol. 30, no. 23, pp. 2644–2658, 2011.
[29]
Y. Hayashita, H. Osada, Y. Tatematsu et al., “A polycistronic MicroRNA cluster, miR-17-92, is overexpressed in human lung cancers and enhances cell proliferation,” Cancer Research, vol. 65, no. 21, pp. 9628–9632, 2005.
[30]
Y. T. Chou, H. H. Lin, Y. C. Lien et al., “EGFR promotes lung tumorigenesis by activating miR-7 through a Ras/ERK/Myc pathway that targets the Ets2 transcriptional repressor ERF,” Cancer Research, vol. 70, no. 21, pp. 8822–8831, 2010.
[31]
M. E. Hatley, D. M. Patrick, M. R. Garcia et al., “Modulation of K-Ras-dependent lung tumorigenesis by MicroRNA-21,” Cancer Cell, vol. 18, no. 3, pp. 282–293, 2010.
[32]
X. Liu, L. F. Sempere, H. Ouyang et al., “MicroRNA-31 functions as an oncogenic microRNA in mouse and human lung cancer cells by repressing specific tumor suppressors,” Journal of Clinical Investigation, vol. 120, no. 4, pp. 1298–1309, 2010.
[33]
J. Lu, G. Getz, E. A. Miska et al., “MicroRNA expression profiles classify human cancers,” Nature, vol. 435, no. 7043, pp. 834–838, 2005.
[34]
M. T. Landi, Y. Zhao, M. Rotunno et al., “MicroRNA expression differentiates histology and predicts survival of lung cancer,” Clinical Cancer Research, vol. 16, no. 2, pp. 430–441, 2010.
[35]
D. Lebanony, H. Benjamin, S. Gilad, et al., “Diagnostic assay based on hsa-miR-205 expression distinguishes squamous from nonsquamous non-small-cell lung carcinoma,” Journal of Clinical Oncology, vol. 27, no. 12, pp. 2030–2037, 2009.
[36]
A. R. Feinstein, N. A. Gelfman, R. Yesner, et al., “Observer variability in the histopathologic diagnosis of lung cancer,” American Review of Respiratory Disease, vol. 101, no. 5, pp. 671–684, 1970.
[37]
J. B. Sorensen, F. R. Hirsch, A. Gazdar, and J. E. Olsen, “Interobserver variability in histopathologic subtyping and grading of pulmonary adenocarcinoma,” Cancer, vol. 71, no. 10, pp. 2971–2976, 1993.
[38]
S. L. Yu, H. Y. Chen, G. C. Chang et al., “MicroRNA signature predicts survival and relapse in lung cancer,” Cancer Cell, vol. 13, no. 1, pp. 48–57, 2008.
[39]
W. Gao, Y. Yu, H. Cao et al., “Deregulated expression of miR-21, miR-143 and miR-181a in non small cell lung cancer is related to clinicopathologic characteristics or patient prognosis,” Biomedicine & Pharmacotherapy, vol. 64, no. 6, pp. 399–408, 2010.
[40]
A. Navarro, T. Diaz, E. Gallardo et al., “Prognostic implications of miR-16 expression levels in resected non-small-cell lung cancer,” Journal of Surgical Oncology, vol. 103, no. 5, pp. 411–415, 2011.
[41]
L. Jiang, Q. Huang, S. Zhang et al., “Hsa-miR-125a-3p and hsa-miR-125a-5p are downregulated in non-small cell lung cancer and have inverse effects on invasion and migration of lung cancer cells,” BMC Cancer, vol. 10, pp. 318–330, 2010.
[42]
M. Saito, A. J. Schetter, S. Mollerup et al., “The association of microRNA expression with prognosis and progression in early-stage, non-small cell lung adenocarcinoma: a retrospective analysis of three cohorts,” Clinical Cancer Research, vol. 17, no. 7, pp. 1875–1882, 2011.
[43]
S. Arora, A. R. Ranade, N. L. Tran et al., “MicroRNA-328 is associated with (non-small) cell lung cancer (NSCLC) brain metastasis and mediates NSCLC migration,” International Journal of Cancer. In press.
[44]
R. Hummel, D. J. Hussey, and J. Haier, “MicroRNAs: predictors and modifiers of chemo- and radiotherapy in different tumour types,” European Journal of Cancer, vol. 46, no. 2, pp. 298–311, 2010.
[45]
S. K. Patnaik, E. Kannisto, S. Knudsen, and S. Yendamuri, “Evaluation of microRNA expression profiles that may predict after surgical resection recurrence of localized stage i non-small cell lung cancer,” Cancer Research, vol. 70, no. 1, pp. 36–44, 2010.
[46]
A. R. Ranade, D. Cherba, S. Sridhar et al., “MicroRNA 92a-2*: a biomarker predictive for chemoresistance and prognostic for survival in patients with small cell lung cancer,” Journal of Thoracic Oncology, vol. 5, no. 8, pp. 1273–1278, 2010.
[47]
J. B. Weidhaas, I. Babar, S. M. Nallur et al., “MicroRNAs as potential agents to alter resistance to cytotoxic anticancer therapy,” Cancer Research, vol. 67, no. 23, pp. 11111–11116, 2007.
[48]
M. Boeri, C. Verri, D. Conte et al., “MicroRNA signatures in tissues and plasma predict development and prognosis of computed tomography detected lung cancer,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 9, pp. 3713–3718, 2011.
[49]
Z. Hu, X. Chen, Y. Zhao et al., “Serum microRNA signatures identified in a genome-wide serum microRNA expression profiling predict survival of non-small-cell lung cancer,” Journal of Clinical Oncology, vol. 28, no. 10, pp. 1721–1726, 2010.
[50]
J. Shen, N. W. Todd, H. Zhang et al., “Plasma microRNAs as potential biomarkers for non-small-cell lung cancer,” Laboratory Investigation, vol. 91, no. 4, pp. 579–587, 2011.
[51]
W. Gao, L. Liu, X. Lu, and Y. Shu, “Circulating microRNAs: possible prediction biomarkers for personalized therapy of non-small-cell lung carcinoma,” Clinical Lung Cancer, vol. 12, no. 1, pp. 14–17, 2011.
[52]
L. Yu, N. W. Todd, L. Xing et al., “Early detection of lung adenocarcinoma in sputum by a panel of microRNA markers,” International Journal of Cancer, vol. 127, no. 12, pp. 2870–2878, 2010.
[53]
R. Duan, C. 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.
[54]
Z. Yu, Z. Li, N. Jolicoeur et al., “Aberrant allele frequencies of the SNPs located in microRNA target sites are potentially associated with human cancers,” Nucleic Acids Research, vol. 35, no. 13, pp. 4535–4541, 2007.
[55]
X. Pu, C. Lu, D. J. Stewart, et al., “MicroRNA-related genetic variants as predictors of early stage non–small cell lung cancer clinical outcomes,” Cancer Epidemiology Biomarkers & Prevention, vol. 20, no. 4, p. 719, 2011.
[56]
Z. Hu, J. Chen, T. Tian et al., “Genetic variants of miRNA sequences and non-small cell lung cancer survival,” Journal of Clinical Investigation, vol. 118, no. 7, pp. 2600–2608, 2008.
[57]
M. Wu, N. Jolicoeur, Z. Li et al., “Genetic variations of microRNAs in human cancer and their effects on the expression of miRNAs,” Carcinogenesis, vol. 29, no. 9, pp. 1710–1716, 2008.
[58]
M. S. Nicoloso, H. Sun, R. Spizzo et al., “Single-nucleotide polymorphisms inside microRNA target sites influence tumor susceptibility,” Molecular and Cellular Pathobiology, vol. 70, no. 7, pp. 2789–2798, 2010.
[59]
B. M. Ryan, A. I. Robles, and C. C. Harris, “Genetic variation in microRNA networks: the implications for cancer research,” Nature Reviews Cancer, vol. 10, no. 6, pp. 389–402, 2010.
[60]
T. Tian, Y. Shu, J. Chen et al., “A functional genetic variant in microRNA-196a2 is associated with increased susceptibility of lung cancer in Chinese,” Cancer Epidemiology Biomarkers & Prevention, vol. 18, no. 4, pp. 1183–1187, 2009.
[61]
J. S. Kim, Y. Y. Choi, G. Jin et al., “Association of a common AGO1 variant with lung cancer risk: a two-stage case-control study,” Molecular Carcinogenesis, vol. 49, no. 10, pp. 913–921, 2010.
[62]
L. J. Chin, E. Ratner, S. Leng et al., “A SNP in a let-7 microRNA complementary site in the KRAS 3'UTR increases non-small cell lung cancer risk,” Cancer Research, vol. 68, no. 20, pp. 8535–8540, 2008.
[63]
M. Rotunno, Y. Zhao, A. W. Bergen et al., “Inherited polymorphisms in the RNA-mediated interference machinery affect microRNA expression and lung cancer survival,” British Journal of Cancer, vol. 103, no. 12, pp. 1870–1874, 2010.
[64]
Z. Liu, A. Sall, and D. Yang, “MicroRNA: an emerging therapeutic target and intervention tool,” International Journal of Molecular Sciences, vol. 9, no. 6, pp. 978–999, 2008.
[65]
C. Li, Y. Feng, G. Coukos, and L. Zhang, “Therapeutic microRNA strategies in human cancer,” The AAPS Journal, vol. 11, no. 4, pp. 747–757, 2009.
[66]
J. Kota, R. R. Chivukula, K. A. O'Donnell et al., “Therapeutic microRNA delivery suppresses tumorigenesis in a murine liver cancer model,” Cell, vol. 137, no. 6, pp. 1005–1017, 2009.
[67]
O. A. Kent, R. R. Chivukula, M. Mullendore et al., “Repression of the miR-143/145 cluster by oncogenic Ras initiates a tumor-promoting feed-forward pathway,” Genes and Development, vol. 24, no. 24, pp. 2754–2759, 2010.
[68]
A. Esquela-Kerscher, P. Trang, J. F. Wiggins et al., “The let-7 microRNA reduces tumor growth in mouse models of lung cancer,” Cell Cycle, vol. 7, no. 6, pp. 759–764, 2008.
[69]
P. Trang, P. P. Medina, J. F. Wiggins et al., “Regression of murine lung tumors by the let-7 microRNA,” Oncogene, vol. 29, no. 11, pp. 1580–1587, 2010.
[70]
J. F. Wiggins, L. Ruffino, K. Kelnar et al., “Development of a lung cancer therapeutic based on the tumor suppressor microRNA-34,” Cancer Research, vol. 70, no. 14, pp. 5923–5930, 2010.
[71]
X. Pan, R. Thompson, X. Meng, et al., “Tumor-targeted RNA-interference: functional non-viral nanovectors,” American Journal of Cancer Research, vol. 1, no. 1, pp. 25–42, 2011.
[72]
P. Li, D. Liu, X. Sun, C. Liu, Y. Liu, and N. Zhang, “A novel cationic liposome formulation for efficient gene delivery via a pulmonary route,” Nanotechnology, vol. 22, no. 24, Article ID 245104, 2011.
[73]
K. C. Vickers, B. T. Palmisano, B. M. Shoucri, R. D. Shamburek, and A. T. Remaley, “MicroRNAs are transported in plasma and delivered to recipient cells by high-density lipoproteins,” Nature Cell Biology, vol. 13, no. 4, pp. 423–433, 2011.
[74]
Y. Chen, X. Zhu, X. Zhang, B. Liu, and L. Huang, “Nanoparticles modified with tumor-targeting scFv deliver siRNA and miRNA for cancer therapy,” Molecular Therapy, vol. 18, no. 9, pp. 1650–1656, 2010.
[75]
Y. Chen, S. R. Bathula, Q. Yang, and L. Huang, “Targeted nanoparticles deliver siRNA to melanoma,” Journal of Investigative Dermatology, vol. 12, no. 12, pp. 2790–2798, 2010.
[76]
S. Davis, S. Propp, S. M. Freier et al., “Potent inhibition of microRNA in vivo without degradation,” Nucleic Acids Research, vol. 37, no. 1, pp. 70–77, 2009.
[77]
H. Peacock, R. V. Fucini, P. Jayalath, et al., “Nucleobase and ribose modifications control immunostimulation by a MicroRNA-122-mimetic RNA,” Journal of American Chemical Society, vol. 133, no. 24, pp. 9200–9203, 2011.
[78]
J. C. Chuang and P. A. Jones, “Epigenetics and microRNAs,” Pediatric Research, vol. 61, no. 5, pp. 24R–29R, 2007.
[79]
M. Fabbri, R. Garzon, A. Cimmino et al., “MicroRNA-29 family reverts aberrant methylation in lung cancer by targeting DNA methyltransferases 3A and 3B,” Proceedings of the National Academy of Sciences of the United States of America, vol. 104, no. 40, pp. 15805–15810, 2007.
