Abstract
microRNAs have been implicated in regulating diverse cellular pathways. Although there is emerging evidence that some microRNAs can function as oncogenes or tumor suppressors, the role of microRNAs in mediating cancer progression remains unexplored. And whether expression levels of a panel of biologically relevant microRNAs can be used as prognostic or predictive biomarkers in radically resected non-small-cell lung carcinoma (NSCLC) patients still needs to be further validated. Our analyses involved two separated, retrospective cohorts. Firstly, microRNA expression profile was performed in a cohort consisted of 128 radically resected NSCLC patients [60 were positive to epidermal growth factor receptor (EGFR) mutation and 68 were negative] and 32 healthy providers to identify EGFR mutation-related microRNAs and to determine their association with survival. In addition, to validate our findings, we used quantitative reverse transcriptase polymerase chain reaction assays to measure microRNAs and assess their association with disease progression, survival, and response to gefitinib in an independent cohort of 201 patients with EGRF mutation. In radically resected NSCLC patients, the expression levels of miR-21, 10b in patients with EGFR mutation were much higher than those without mutation. We used Cox proportional-hazards regression to evaluate the effect of treatment on survival. In both univariate and multivariate analyses, gefitinib was associated with a significant improvement in overall survival in patients with reduced miR-21 expression. Thus, miR-21 expression emerged as an independent predictor of the response to gefitinib. Additionally, miR-10b is highly expressed in progressive disease compared with complete remission or stable disease (P < 0.001). However, miR-21 expression has no significant prognosis for disease progression (P = 0.720). Meanwhile, when overall survival was considered as the end point, miR-10b did not have a significant difference between different subgroups (P = 0.634). The expression patterns of microRNAs differ significantly between patients with positive and negative EGFR mutation. And the expression status of miR-21 and 10b in such patients is associated with disease progression, survival, and response to adjuvant therapy with gefitinib.
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References
Reck M. What future opportunities may immuno-oncology provide for improving the treatment of patients with lung cancer? Ann Oncol. 2012;23(Suppl 8):viii28–34.
Tanner NT, Mehta H, Silvestri GA. New testing for lung cancer screening. Oncology (Williston Park). 2012;26:176–82.
Yanagisawa K, Shyr Y, Xu BJ, Massion PP, Larsen PH, White BC, et al. Proteomic patterns of tumour subsets in non-small-cell lung cancer. Lancet. 2003;362:433–9.
Hirsch FR, Janne PA, Eberhardt WE, Cappuzzo F, Thatcher N, Pirker R, et al. Epidermal growth factor receptor inhibition in lung cancer: status 2012. J Thorac Oncol. 2013;8:373–84.
Jiang YW, Chen LA. microRNAs as tumor inhibitors, oncogenes, biomarkers for drug efficacy and outcome predictors in lung cancer (review). Mol Med Rep. 2012;5:890–4.
Fukaya T, Tomari Y. MicroRNAs mediate gene silencing via multiple different pathways in drosophila. Mol Cell. 2012;48:825–36.
Forstemann K, Horwich MD, Wee L, Tomari Y, Zamore PD. Drosophila microRNAs are sorted into functionally distinct argonaute complexes after production by dicer-1. Cell. 2007;130:287–97.
Rudnicki A, Avraham KB. microRNAs: the art of silencing in the ear. EMBO Mol Med. 2012;4:849–59.
Wang Y, Taniguchi T. MicroRNAs and DNA damage response: implications for cancer therapy. Cell Cycle. 2013;12:32–42.
Harquail J, Benzina S, Robichaud GA. MicroRNAs and breast cancer malignancy: an overview of miRNA-regulated cancer processes leading to metastasis. Cancer Biomark. 2012;11:269–80.
Huppi K, Volfovsky N, Runfola T, Jones TL, Mackiewicz M, Martin SE, et al. The identification of microRNAs in a genomically unstable region of human chromosome 8q24. Mol Cancer Res. 2008;6:212–21.
Cheung TH, Man KN, Yu MY, Yim SF, Siu NS, Lo KW, et al. Dysregulated microRNAs in the pathogenesis and progression of cervical neoplasm. Cell Cycle. 2012;11:2876–84.
Boeri M, Pastorino U, Sozzi G. Role of microRNAs in lung cancer: microRNA signatures in cancer prognosis. Cancer J. 2012;18:268–74.
Ellison G, Donald E, McWalter G, Knight L, Fletcher L, Sherwood J, et al. A comparison of ARMS and DNA sequencing for mutation analysis in clinical biopsy samples. J Exp Clin Cancer Res. 2010;29:132.
Reungwetwattana T, Weroha SJ, Molina JR. Oncogenic pathways, molecularly targeted therapies, and highlighted clinical trials in non-small-cell lung cancer (NSCLC). Clin Lung Cancer. 2012;13:252–66.
Costa DB, Kobayashi S. Are exon 19 deletions and L858R EGFR mutations in non-small-cell lung cancer clinically different? Br J Cancer. 2007; 96:399; author reply 400.
Smouse JH, Cibas ES, Janne PA, Joshi VA, Zou KH, Lindeman NI. EGFR mutations are detected comparably in cytologic and surgical pathology specimens of nonsmall cell lung cancer. Cancer. 2009;117:67–72.
Yun CH, Boggon TJ, Li Y, Woo MS, Greulich H, Meyerson M, et al. Structures of lung cancer-derived EGFR mutants and inhibitor complexes: mechanism of activation and insights into differential inhibitor sensitivity. Cancer Cell. 2007;11:217–27.
Zhou BB, Peyton M, He B, Liu C, Girard L, Caudler E, et al. Targeting ADAM-mediated ligand cleavage to inhibit HER3 and EGFR pathways in non-small cell lung cancer. Cancer Cell. 2006;10:39–50.
Zhu H, Acquaviva J, Ramachandran P, Boskovitz A, Woolfenden S, Pfannl R, et al. Oncogenic EGFR signaling cooperates with loss of tumor suppressor gene functions in gliomagenesis. Proc Natl Acad Sci USA. 2009;106:2712–6.
Cho WC, Chow AS, Au JS. Restoration of tumour suppressor hsa-miR-145 inhibits cancer cell growth in lung adenocarcinoma patients with epidermal growth factor receptor mutation. Eur J Cancer. 2009;45:2197–206.
Chou YT, Lin HH, Lien YC, Wang YH, Hong CF, Kao YR, et al. EGFR promotes lung tumorigenesis by activating miR-7 through a Ras/ERK/Myc pathway that targets the Ets2 transcriptional repressor ERF. Cancer Res. 2010;70:8822–31.
Seike M, Goto A, Okano T, Bowman ED, Schetter AJ, Horikawa I, et al. MiR-21 is an EGFR-regulated anti-apoptotic factor in lung cancer in never-smokers. Proc Natl Acad Sci USA. 2009;106:12085–90.
Ma X, Kumar M, Choudhury SN, Becker Buscaglia LE, Barker JR, Kanakamedala K, et al. Loss of the miR-21 allele elevates the expression of its target genes and reduces tumorigenesis. Proc Natl Acad Sci USA. 2011;108:10144–9.
Iliopoulos D, Jaeger SA, Hirsch HA, Bulyk ML, Struhl K. STAT3 activation of miR-21 and miR-181b-1 via PTEN and CYLD are part of the epigenetic switch linking inflammation to cancer. Mol Cell. 2010;39:493–506.
Kratz JR, He J, Van Den Eeden SK, Zhu ZH, Gao W, Pham PT, et al. A practical molecular assay to predict survival in resected non-squamous, non-small-cell lung cancer: development and international validation studies. Lancet. 2012;379:823–32.
Yanaihara N, Caplen N, Bowman E, Seike M, Kumamoto K, Yi M, et al. Unique microRNA molecular profiles in lung cancer diagnosis and prognosis. Cancer Cell. 2006;9:189–98.
Raponi M, Dossey L, Jatkoe T, Wu X, Chen G, Fan H, et al. MicroRNA classifiers for predicting prognosis of squamous cell lung cancer. Cancer Res. 2009;69:5776–83.
Acknowledgments
This study is supported partly by the grant of Shandong Tackle Key Problems in Science and Technology (2010GSF10245), Shandong Excellent Young Scientist Research Award Fund Project (BS2010YY013), and Shandong Natural Science Fund (Y2008C48; ZR2009CQ040).
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There is no conflict of interest for any of the authors in any aspects of the article.
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Shen, Y., Tang, D., Yao, R. et al. microRNA expression profiles associated with survival, disease progression, and response to gefitinib in completely resected non-small-cell lung cancer with EGFR mutation. Med Oncol 30, 750 (2013). https://doi.org/10.1007/s12032-013-0750-1
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DOI: https://doi.org/10.1007/s12032-013-0750-1