Abstract
Purpose
We investigated whether miRNA expression profiles can distinguish and predict outcome of non-small-cell lung carcinoma (NSCLC) patients with different histological subtypes.
Methods
High-throughput microarray was used to measure miRNA expression levels in six NSCLC samples. Subsequently, quantitative reverse transcription polymerase chain reaction (qRT-PCR) was used to verify findings in an independent set of 54 squamous-cell lung carcinomas (SCC), 51 lung adenocarcinomas (AD), and paired adjacent non-neoplastic lung tissue.
Results
We showed that, compared to adjacent non-neoplastic lung tissues, the expressions of miR-125a-5p and let-7e were decreased in AD and SCC samples, while increased expressions of miR-93, miR-205, and miR-221 were observed in SCC samples. In addition, miR-205 expression was significantly higher in SCC patients with lymph node metastasis. Lower let-7e expression was associated with lymph node metastasis, >3 cm tumor size, and differentiation of the NSCLC AD subtype. High levels of miR-100 expression also correlated with the AD subtype in current smokers. Moreover, induction of miR-93 and miR-205 expressions and reduction of let-7e were strongly associated with shorter overall survival in SCC patients, whereas AD patient survival was only associated with reduced let-7e.
Conclusions
We identified differential expression profiles of miRNAs in AD and SCC. More importantly, in addition to morphology and immunocytochemistry approaches, we report that miR-93, miR-205, miR-221, and let-7e may represent novel biomarkers for differential diagnosis and prognosis of certain NSCLC subtypes or be new targets of histology-specific treatments. Furthermore, our results suggest a strong correlation between high expression of miR-100 and AD patients with history of heavy smoking.
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References
Bishop JA, Benjamin H, Cholakh H, Chajut A, Clark DP, Westra WH (2010) Accurate classification of non-small cell lung carcinoma using a novel microRNA-based approach. Clin Cancer Res 16(2):610–619
Boffetta P, Jayaprakash V, Yang P et al (2011) Tobacco smoking as a risk factor of bronchioloalveolar carcinoma of the lung: pooled analysis of seven case–control studies in the international lung cancer consortium (ILCCO). Cancer Causes Control 22:1–7
Frost G, Darnton A, Harding AH (2011) The effect of smoking on the risk of lung cancer mortality for asbestos workers in Great Britain. Ann Occup Hyg 55(3):239–241
Gregory PA, Bert AG, Paterson EL et al (2008) The miR-200 family and miR-205 regulate epithelial to mesenchymal transition by targeting ZEB1 and SIP1. Nat Cell Biol 10(5):593–601
Hecht SS (1999) Tobacco smoke carcinogens and lung cancer. J Natl Cancer Inst 91(14):1194–1210
Hirsch FR, Spreafico A, Novello S, Wood MD, Simms L, Papotti M (2008) The prognostic and predictive role of histology in advanced non-small cell lung cancer: a literature review. J Thorac Oncol 3(12):1468–1481
Izzotti A, Calin GA, Arrigo P, Steele VE, Croce CM, De Flora S (2009) Downregulation of microRNA expression in the lungs of rats exposed to cigarette smoke. FASEB J 23(3):806–812
Johnson CD, Esquela-Kerscher A, Stefani G et al (2007) The let-7 microRNA represses cell proliferation pathways in human cells. Cancer Res 67(16):7713–7722
Jorda M, Gomez-Fernandez C, Garcia M et al (2009) P63 differentiates subtypes of non-small cell carcinomas of lung in cytologic samples. Cancer Cytopathol 117(1):46–50
Landi MT, Zhao Y, Rotunno M et al (2010) MicroRNA expression differentiates histology and predicts survival of lung cancer. Clin Cancer Res 16(2):430–441
Lebanony D, Benjamin H, Gilad S et al (2009) Diagnostic assay based on hsa-miR-205 expression distinguishes squamous from nonsquamous non-small-cell lung carcinoma. J Clin Oncol 27(12):2030–2037
Lee YS, Dutta A (2007) The tumor suppressor microRNA let-7 represses the HMGA2 oncogene. Genes Dev 21(9):1025–1030
Li Y, VandenBoom TG, Kong D et al (2009) Up-regulation of miR-200 and let-7 by natural agents leads to the reversal of epithelial-to-mesenchymal transition in gemcitabine-resistant pancreatic cancer cells. Cancer Res 69(16):6704–6712
Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-[delta][delta] CT method. Methods 25(4):402–408
Lu J, Getz G, Miska EA et al (2005) MicroRNA expression profiles classify human cancers. Nature 435(7043):834–838
Majid S, Dar AA, Saini S et al (2010) MicroRNA-205 directed transcriptional activation of tumor suppressor genes in prostate cancer. Cancer 116(24):5637–5649
Medina PP, Slack FJ (2008) MicroRNAs and cancer: an overview. Cell Cycle 7:2485–2492
Miller YE (2005) Pathogenesis of lung cancer: 100 year report. Am J Respir Cell Mol Biol 33(3):216–223
Ragusa M, Majorana A, Statello L et al (2010) Specific alterations of microRNA transcriptome and global network structure in colorectal carcinoma after cetuximab treatment. Mol Cancer Ther 9(12):3396–3403
Raponi M, Dossey L, Jatkoe T et al (2009) MicroRNA classifiers for predicting prognosis of squamous cell lung cancer. Cancer Res 69(14):5583–5776
Scagliotti GV, Parikh P, von Pawel J et al (2008) Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 26(21):3543–3551
Takamizawa J, Konishi H, Yanagisawa K et al (2004) Reduced expression of the let-7 microRNAs in human lung cancers in association with shortened postoperative survival. Cancer Res 64(11):3753–3756
Thomson JM, Newman M, Parker JS, Morin-Kensicki EM, Wright T, Hammond SM (2006) Extensive post-transcriptional regulation of microRNAs and its implications for cancer. Genes Dev 20(16):2202–2207
Van Pottelberge GR, Mestdagh P, Bracke KR et al (2010) MicroRNA expression in induced sputum of smokers and patients with chronic obstructive pulmonary disease. Am J Respir Crit Care Med 183:898–906
Vescovo VD, Cantaloni C, Cucino A et al (2011) MiR-205 expression levels in non-small cell lung cancer do not always distinguish adenocarcinomas from squamous cell carcinomas. Am J Surg Pathol 35(2):268–275
Wang B, Howel P, Bruheim S et al (2011) Systematic evaluation of three microRNA profiling platforms: microarray, beads array, and quantitative real-time PCR array. PLoS One 6(2):e17167
Xing L, Todd NW, Yu L, Fang HB, Jiang F (2010) Early detection of squamous cell lung cancer in sputum by a panel of microRNA markers. Mod Pathol 23(8):1157–1164
Yanaihara N, Caplen N, Bowman E et al (2006) Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell 9(3):189–198
Yu SL, Chen HY, Chang GC et al (2008) MicroRNA signature predicts survival and relapse in lung cancer. Cancer Cell 13(1):48–57
Acknowledgments
This research was supported by grants from the Medical Science Foundation of Zhejiang Province (No. 2009A210), the Science and Technology Program of Zhoushan (Nos. 20081059 and 091042), and the Medical Science Foundation of Zhoushan (No. 2009B03).
Conflict of interest
The authors declare no conflict of interests exist in relation to the publication of this study.
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Zhang, YK., Zhu, WY., He, JY. et al. miRNAs expression profiling to distinguish lung squamous-cell carcinoma from adenocarcinoma subtypes. J Cancer Res Clin Oncol 138, 1641–1650 (2012). https://doi.org/10.1007/s00432-012-1240-0
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DOI: https://doi.org/10.1007/s00432-012-1240-0