[en] Aberrant expression of microRNA-146a (miR-146a) has been reported to be involved in the development and progression of various types of cancers. However, its role in non-small cell lung cancer (NSCLC) has not been elucidated. The aim of this study was to investigate the contribution of miR-146a to various aspects of the malignant phenotype of human NSCLCs. In functional experiments, miR-146a suppressed cell growth, induced cellular apoptosis and inhibited EGFR downstream signaling in five NSCLC cell lines (H358, H1650, H1975, HCC827 and H292). miR-146a also inhibited the migratory capacity of these NSCLC cells. On the other hand, miR-146a enhanced the inhibition of cell proliferation by drugs targeting EGFR, including both TKIs (gefitinib, erlotinib, and afatinib) and a monoclonal antibody (cetuximab). These effects were independent of the EGFR mutation status (wild type, sensitizing mutation or resistance mutation), but were less potent compared to the effects of siRNA targeting of EGFR. Our results suggest that these effects of miR-146a are due to its targeting of EGFR and NF-kappaB signaling. We also found, in clinical formalin fixed paraffin embedded (FFPE) lung cancer samples, that low expression of miR-146a was correlated with advanced clinical TNM stages and distant metastasis in NSCLC (P<0.05). The patients with high miR-146a expression in their tumors showed longer progression-free survival (25.6 weeks in miR-146a high patients vs. 4.8 weeks in miR-146a low patients, P<0.05). miR-146a is therefore a strong candidate prognostic biomarker in NSCLC. Thus inducing miR-146a might be a therapeutic strategy for NSCLC.
Disciplines :
Oncology
Author, co-author :
Chen, Gang
Umelo, Ijeoma ; Université de Liège > Département des sciences biomédicales et précliniques > GIGA-R : Labo de recherche sur les métastases
Lv, Shasha
Teugels, Erik
Fostier, Karel
Kronenberger, Peter
Dewaele, Alex
Sadones, Jan
Geers, Caroline
De Greve, Jacques
Language :
English
Title :
miR-146a inhibits cell growth, cell migration and induces apoptosis in non-small cell lung cancer cells.
Publication date :
2013
Journal title :
PLoS ONE
eISSN :
1932-6203
Publisher :
Public Library of Science, United States - California
Pfister DG, Johnson DH, Azzoli CG, Sause W, Smith TJ, et al. (2004) American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 22: 330-353.
Yilmaz A, Damadoglu E, Salturk C, Okur E, Tuncer LY, et al. (2008) Delays in the diagnosis and treatment of primary lung cancer: are longer delays associated with advanced pathological stage? Ups J Med Sci 113: 287-296.
Custodio A, Mendez M, Provencio M, (2011) Targeted therapies for advanced non-small-cell lung cancer: Current status and future implications. Cancer Treat Rev.
Somaiah N, Simon GR, (2010) Molecular targeted agents and biologic therapies for non-small cell lung cancer. J Thorac Oncol 5: S434-454.
Jung JH, Jung CK, Choi HJ, Jun KH, Yoo J, et al. (2009) Diagnostic utility of expression of claudins in non-small cell lung cancer: different expression profiles in squamous cell carcinomas and adenocarcinomas. Pathol Res Pract 205: 409-416.
Papagiannakopoulos T, Kosik KS, (2008) MicroRNAs: regulators of oncogenesis and stemness. BMC Med 6: 15.
Hummel R, Hussey DJ, Haier J, (2010) MicroRNAs: predictors and modifiers of chemo- and radiotherapy in different tumour types. Eur J Cancer 46: 298-311.
He H, Jazdzewski K, Li W, Liyanarachchi S, Nagy R, et al. (2005) The role of microRNA genes in papillary thyroid carcinoma. Proc Natl Acad Sci USA 102: 19075-19080.
Pacifico F, Crescenzi E, Mellone S, Iannetti A, Porrino N, et al. (2010) Nuclear factor-{kappa}B contributes to anaplastic thyroid carcinomas through up-regulation of miR-146a. J Clin Endocrinol Metab 95: 1421-1430.
Wang X, Tang S, Le SY, Lu R, Rader JS, et al. (2008) Aberrant expression of oncogenic and tumor-suppressive microRNAs in cervical cancer is required for cancer cell growth. PLoS One 3: e2557.
Lin SL, Chiang A, Chang D, Ying SY, (2008) Loss of mir-146a function in hormone-refractory prostate cancer. RNA 14: 417-424.
Li Y, Vandenboom TG, Wang Z, Kong D, Ali S, et al. (2010) miR-146a suppresses invasion of pancreatic cancer cells. Cancer Res 70: 1486-1495.
Kogo R, Mimori K, Tanaka F, Komune S, Mori M, (2011) Clinical significance of miR-146a in gastric cancer cases. Clin Cancer Res 17: 4277-4284.
Hou Z, Xie L, Yu L, Qian X, Liu B, (2011) MicroRNA-146a is down-regulated in gastric cancer and regulates cell proliferation and apoptosis. Med Oncol.
Scapoli L, Palmieri A, Lo Muzio L, Pezzetti F, Rubini C, et al. (2010) MicroRNA expression profiling of oral carcinoma identifies new markers of tumor progression. Int J Immunopathol Pharmacol 23: 1229-1234.
Bhaumik D, Scott GK, Schokrpur S, Patil CK, Campisi J, et al. (2008) Expression of microRNA-146 suppresses NF-kappaB activity with reduction of metastatic potential in breast cancer cells. Oncogene 27: 5643-5647.
Griffiths-Jones S, Saini HK, van Dongen S, Enright AJ, (2008) miRBase: tools for microRNA genomics. Nucleic Acids Res 36: D154-158.
Hurst DR, Edmonds MD, Scott GK, Benz CC, Vaidya KS, et al. (2009) Breast cancer metastasis suppressor 1 up-regulates miR-146, which suppresses breast cancer metastasis. Cancer Res 69: 1279-1283.
Harari PM, Allen GW, Bonner JA, (2007) Biology of interactions: antiepidermal growth factor receptor agents. J Clin Oncol 25: 4057-4065.
Sethi G, Ahn KS, Chaturvedi MM, Aggarwal BB, (2007) Epidermal growth factor (EGF) activates nuclear factor-kappaB through IkappaBalpha kinase-independent but EGF receptor-kinase dependent tyrosine 42 phosphorylation of IkappaBalpha. Oncogene 26: 7324-7332.
Paik JH, Jang JY, Jeon YK, Kim WY, Kim TM, et al. (2011) MicroRNA-146a downregulates NFkappaB activity via targeting TRAF6 and functions as a tumor suppressor having strong prognostic implications in NK/T cell lymphoma. Clin Cancer Res 17: 4761-4771.
Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, et al. (2005) MicroRNA expression profiles classify human cancers. Nature 435: 834-838.
Chen G, Kronenberger P, Teugels E, Adaku Umelo I, De Greve J, (2012) Targeting the epidermal growth factor receptor in non-small cell lung cancer cells: the effect of combining RNA interference with tyrosine kinase inhibitors or cetuximab. BMC Med 10: 28.
Chen G, Kronenberger P, Teugels E, Umelo IA, De Greve J, (2012) Effect of siRNAs targeting T790M mutation and wild type EGFR in non-small cell lung cancer cell line resistant to gefitinib or erlotinib. Biochem Biophys Res Commun.
Chen G, Kronenberger P, Teugels E, De Grève J, (2011) Influence of RT-qPCR primer position on EGFR interference efficacy in lung cancer cells. Biol Proced Online 13: 1.
Chen G, Kronenberger P, Umelo IA, Teugels E, De Grève J, (2010) Quantification of epidermal growth factor receptor T790M mutant transcripts in lung cancer cells by real-time reverse transcriptase-quantitative polymerase chain reaction. Anal Biochem 398: 266-268.
Chen G, Kronenberger P, Teugels E, De Greve J, (2011) Influence of RT-qPCR primer position on EGFR interference efficacy in lung cancer cells. Biol Proced Online 13: 1.
Livak KJ, Schmittgen TD, (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) Method. Methods 25: 402-408.
Suhnel J, (1996) Zero interaction response surfaces for combined-action assessment. Food Chem Toxicol 34: 1151-1153.
Koivusalo R, Krausz E, Helenius H, Hietanen S, (2005) Chemotherapy compounds in cervical cancer cells primed by reconstitution of p53 function after short interfering RNA-mediated degradation of human papillomavirus 18 E6 mRNA: opposite effect of siRNA in combination with different drugs. Mol Pharmacol 68: 372-382.
Chou TC, (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58: 621-681.
Larner-Svensson HM, Williams AE, Tsitsiou E, Perry MM, Jiang X, et al. (2010) Pharmacological studies of the mechanism and function of interleukin-1beta-induced miRNA-146a expression in primary human airway smooth muscle. Respir Res 11: 68.
Cui JG, Li YY, Zhao Y, Bhattacharjee S, Lukiw WJ, (2010) Differential regulation of interleukin-1 receptor-associated kinase-1 (IRAK-1) and IRAK-2 by microRNA-146a and NF-kappaB in stressed human astroglial cells and in Alzheimer disease. J Biol Chem 285: 38951-38960.
Lu LF, Boldin MP, Chaudhry A, Lin LL, Taganov KD, et al. (2010) Function of miR-146a in controlling Treg cell-mediated regulation of Th1 responses. Cell 142: 914-929.
Boominathan L, (2010) The guardians of the genome (p53, TA-p73, and TA-p63) are regulators of tumor suppressor miRNAs network. Cancer Metastasis Rev 29: 613-639.
Sos ML, Koker M, Weir BA, Heynck S, Rabinovsky R, et al. (2009) PTEN loss contributes to erlotinib resistance in EGFR-mutant lung cancer by activation of Akt and EGFR. Cancer Res 69: 3256-3261.
Shimamura T, Lowell AM, Engelman JA, Shapiro GI, (2005) Epidermal growth factor receptors harboring kinase domain mutations associate with the heat shock protein 90 chaperone and are destabilized following exposure to geldanamycins. Cancer Res 65: 6401-6408.
Vinci S, Gelmini S, Pratesi N, Conti S, Malentacchi F, et al. (2011) Genetic variants in miR-146a, miR-149, miR-196a2, miR-499 and their influence on relative expression in lung cancers. Clin Chem Lab Med.
Pichler K, Schneider G, Grassmann R, (2008) MicroRNA miR-146a and further oncogenesis-related cellular microRNAs are dysregulated in HTLV-1-transformed T lymphocytes. Retrovirology 5: 100.
Starczynowski DT, Kuchenbauer F, Argiropoulos B, Sung S, Morin R, et al. (2010) Identification of miR-145 and miR-146a as mediators of the 5q- syndrome phenotype. Nat Med 16: 49-58.
Post SM, Quintas-Cardama A, (2010) Closing in on the pathogenesis of the 5q- syndrome. Expert Rev Anticancer Ther 10: 655-658.
Thu KL, Vucic EA, Chari R, Zhang W, Lockwood WW, et al. (2012) Lung adenocarcinoma of never smokers and smokers harbor differential regions of genetic alteration and exhibit different levels of genomic instability. PLoS One 7: e33003.
Umelo IA, De Wever O, Teugels E, Bracke M, De Grève J, (2010) Effects of EGFR inhibition with tyrosine kinase inhibitors on invasive properties of EGFR mutant and wild type lung cancer cells. European Journal of Cancer 8: 68.
