miR-223 enhances the sensitivity of non-small cell lung cancer cells to erlotinib by targeting the insulin-like growth factor-1 receptor

Zhao,Feng-Yi; Han,Jing; Chen,Xie-Wan; Wang,Jiang; Wang,Xu-Dong; Sun,Jian-Guo; Chen,Zheng-Tang

doi:10.3892/ijmm.2016.2588

miR-223 enhances the sensitivity of non-small cell lung cancer cells to erlotinib by targeting the insulin-like growth factor-1 receptor

Authors:
- Feng-Yi Zhao
- Jing Han
- Xie-Wan Chen
- Jiang Wang
- Xu-Dong Wang
- Jian-Guo Sun
- Zheng-Tang Chen
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Affiliations: Cancer Institute of PLA, Xinqiao Hospital, Third Military Medical University, Chongqing 400037, P.R. China, Medical English Department, College of Basic Medicine, Third Military Medical University, Chongqing 400038, P.R. China
Published online on: May 13, 2016 https://doi.org/10.3892/ijmm.2016.2588
Pages: 183-191
Copyright: © Zhao et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Lung cancer is the leading cause of cancer-related fatalities worldwide, and non-small cell lung cancer (NSCLC) is the main pathological type. MicroRNAs (miRNAs or miRs) are a class of small non-coding RNAs, which are involved in tumor initiation and progression. miR‑223 is a tumor suppressor miRNA that has been reported in various types of cancer, including lung cancer. In the present study, to characterize the biological behavior of miR‑223 in NSCLC, we established an miR‑223 overexpression model in erlotinib-resistant PC‑9 (PC‑9/ER) cells by infection with lentivirus to induce the overexpression of miR‑223. As a result, miR‑223 enhanced the sensitivity of the PC‑9/ER cells to erlotinib by inducing apoptosis in vitro. Additionally, in vivo experiments were performed using nude mice which were injected with the cancer cells [either the PC‑9 (not resistant), PC‑9/ER, or the PC‑9/ER cells infected with miR‑223)]. We found that the tumor volumes were reduced in the rats injected with the cells infected with miR‑223. To further explore the underlying mechanisms, reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis were used to identify the target molecules of miR‑223. miR‑223 was demonstrated to act as a local regulator of insulin-like growth factor-1 receptor (IGF-1R) in the acquired resistance to tyrosine kinase inhibitors (TKIs). Notably, the οverexpression of IGF-1R in NSCLC was downregulated by miR‑223, and the activation of Akt/S6, the downstream pathway, was also inhibited. The inhibition of IGF-1R by miR‑223 was attenuated by exogenous IGF-1 expression. Therefore, miR‑223 may regulate the acquired resistance of PC‑9/ER cells to erlotinib by targeting the IGF-1R/Akt/S6 signaling pathway. The overexpression of miR‑223 may partially reverse the acquired resistance to epidermal growth factor receptor-TKIs, thus, providing a potential therapeutic strategy for TKI-resistant NSCLC.

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1	Jemal A, Siegel R, Xu J and Ward E: Cancer statistics, 2010. CA Cancer J Clin. 60:277–300. 2010. View Article : Google Scholar : PubMed/NCBI
2	Allemani C, Weir HK, Carreira H, Harewood R, Spika D, Wang XS, Bannon F, Ahn JV, Johnson CJ, Bonaventure A, et al CONCORD Working Group: Global surveillance of cancer survival 1995–2009: Analysis of individual data for 25,676,887 patients from 279 population-based registries in 67 countries (CONCORD-2). Lancet. 385:977–1010. 2015. View Article : Google Scholar
3	Larsen JE and Minna JD: Molecular biology of lung cancer: Clinical implications. Clin Chest Med. 32:703–740. 2011. View Article : Google Scholar : PubMed/NCBI
4	Engelman JA, Zejnullahu K, Mitsudomi T, Song Y, Hyland C, Park JO, Lindeman N, Gale CM, Zhao X, Christensen J, et al: MET amplification leads to gefitinib resistance in lung cancer by activating ERBB3 signaling. Science. 316:1039–1043. 2007. View Article : Google Scholar : PubMed/NCBI
5	Morgillo F, Kim WY, Kim ES, Ciardiello F, Hong WK and Lee HY: Implication of the insulin-like growth factor-IR pathway in the resistance of non-small cell lung cancer cells to treatment with gefitinib. Clin Cancer Res. 13:2795–2803. 2007. View Article : Google Scholar : PubMed/NCBI
6	Del Vescovo V and Denti MA: microRNA and lung cancer. Adv Exp Med Biol. 889:153–177. 2015. View Article : Google Scholar : PubMed/NCBI
7	Lagos-Quintana M, Rauhut R, Lendeckel W and Tuschl T: Identification of novel genes coding for small expressed RNAs. Science. 294:853–858. 2001. View Article : Google Scholar : PubMed/NCBI
8	Del Vescovo V, Grasso M, Barbareschi M and Denti MA: MicroRNAs as lung cancer biomarkers. World J Clin Oncol. 5:604–620. 2014. View Article : Google Scholar : PubMed/NCBI
9	Lee CT, Risom T and Strauss WM: MicroRNAs in mammalian development. Birth Defects Res C Embryo Today. 78:129–139. 2006. View Article : Google Scholar : PubMed/NCBI
10	Bueno MJ, Pérez de Castro I and Malumbres M: Control of cell proliferation pathways by microRNAs. Cell Cycle. 7:3143–3148. 2008. View Article : Google Scholar : PubMed/NCBI
11	Jovanovic M and Hengartner MO: miRNAs and apoptosis: RNAs to die for. Oncogene. 25:6176–6187. 2006. View Article : Google Scholar : PubMed/NCBI
12	Mestdagh P, Hartmann N, Baeriswyl L, Andreasen D, Bernard N, Chen C, Cheo D, D'Andrade P, DeMayo M, Dennis L, et al: Evaluation of quantitative miRNA expression platforms in the microRNA quality control (miRQC) study. Nat Methods. 11:809–815. 2014. View Article : Google Scholar : PubMed/NCBI
13	Garofalo M, Quintavalle C, Di Leva G, Zanca C, Romano G, Taccioli C, Liu CG, Croce CM and Condorelli G: MicroRNA signatures of TRAIL resistance in human non-small cell lung cancer. Oncogene. 27:3845–3855. 2008. View Article : Google Scholar : PubMed/NCBI
14	Wong QW, Lung RW, Law PT, Lai PB, Chan KY, To KF and Wong N: MicroRNA-223 is commonly repressed in hepatocellular carcinoma and potentiates expression of Stathmin1. Gastroenterology. 135:257–269. 2008. View Article : Google Scholar : PubMed/NCBI
15	Jia CY, Li HH, Zhu XC, Dong YW, Fu D, Zhao QL, Wu W and Wu XZ: MiR-223 suppresses cell proliferation by targeting IGF-1R. PLoS One. 6:e270082011. View Article : Google Scholar : PubMed/NCBI
16	Nian W, Ao X, Wu Y, Huang Y, Shao J, Wang Y, Chen Z, Chen F and Wang D: miR-223 functions as a potent tumor suppressor of the Lewis lung carcinoma cell line by targeting insulin-like growth factor-1 receptor and cyclin-dependent kinase 2. Oncol Lett. 6:359–366. 2013.PubMed/NCBI
17	Peled N, Wynes MW, Ikeda N, Ohira T, Yoshida K, Qian J, Ilouze M, Brenner R, Kato Y, Mascaux C and Hirsch FR: Insulin-like growth factor-1 receptor (IGF-1R) as a biomarker for resistance to the tyrosine kinase inhibitor gefitinib in non-small cell lung cancer. Cell Oncol (Dordr). 36:277–288. 2013. View Article : Google Scholar
18	Baserga R, Peruzzi F and Reiss K: The IGF-1 receptor in cancer biology. Int J Cancer. 107:873–877. 2003. View Article : Google Scholar : PubMed/NCBI
19	Pollak MN, Schernhammer ES and Hankinson SE: Insulin-like growth factors and neoplasia. Nat Rev Cancer. 4:505–518. 2004. View Article : Google Scholar : PubMed/NCBI
20	Wang Q, Zhao DY, Xu H, Zhou H, Yang QY, Liu F and Zhou GP: Downregulation of microRNA-223 promotes degranulation via the PI3K/Akt pathway by targeting IGF-1R in mast cells. PLoS One. 10:e01235752015. View Article : Google Scholar
21	Yuan Y, Shen Y, Xue L and Fan H: miR-140 suppresses tumor growth and metastasis of non-small cell lung cancer by targeting insulin-like growth factor 1 receptor. PLoS One. 8:e736042013. View Article : Google Scholar : PubMed/NCBI
22	Agulló-Ortuño MT, Díaz-García CV, Agudo-López A, Pérez C, Cortijo A, Paz-Ares L, López-Ríos F, Pozo F, de Castro J and López Martín JA: Relevance of insulin-like growth factor 1 receptor gene expression as a prognostic factor in non-small-cell lung cancer. J Cancer Res Clin Oncol. 141:43–53. 2015. View Article : Google Scholar
23	Scherr M, Venturini L and Eder M: Lentiviral vector-mediated expression of pre-miRNAs and antagomiRs. Methods Mol Biol. 614:175–185. 2010. View Article : Google Scholar : PubMed/NCBI
24	Ryan BM, Robles AI and Harris CC: Genetic variation in microRNA networks: The implications for cancer research. Nat Rev Cancer. 10:389–402. 2010. View Article : Google Scholar : PubMed/NCBI
25	Chen CZ, Li L, Lodish HF and Bartel DP: MicroRNAs modulate hematopoietic lineage differentiation. Science. 303:83–86. 2004. View Article : Google Scholar
26	Yang W, Lan X, Li D, Li T and Lu S: MiR-223 targeting MAFB suppresses proliferation and migration of nasopharyngeal carcinoma cells. BMC Cancer. 15:4612015. View Article : Google Scholar : PubMed/NCBI
27	Yu YH, Zhang L, Wu DS, Zhang Z, Huang FF, Zhang J, Chen XP, Liang DS, Zeng H and Chen FP: MiR-223 regulates human embryonic stem cell differentiation by targeting the IGF-1R/Akt signaling pathway. PLoS One. 8:e787692013. View Article : Google Scholar : PubMed/NCBI
28	Sanfiorenzo C, Ilie MI, Belaid A, Barlési F, Mouroux J, Marquette CH, Brest P and Hofman P: Two panels of plasma microRNAs as non-invasive biomarkers for prediction of recurrence in resectable NSCLC. PLoS One. 8:e545962013. View Article : Google Scholar : PubMed/NCBI
29	Heegaard NH, Schetter AJ, Welsh JA, Yoneda M, Bowman ED and Harris CC: Circulating micro-RNA expression profiles in early stage nonsmall cell lung cancer. Int J Cancer. 130:1378–1386. 2012. View Article : Google Scholar
30	Yamasaki F, Johansen MJ, Zhang D, Krishnamurthy S, Felix E, Bartholomeusz C, Aguilar RJ, Kurisu K, Mills GB, Hortobagyi GN and Ueno NT: Acquired resistance to erlotinib in A-431 epidermoid cancer cells requires downregulation of MMAC1/PTEN and upregulation of phosphorylated Akt. Cancer Res. 67:5779–5788. 2007. View Article : Google Scholar : PubMed/NCBI
31	Bohula EA, Playford MP and Macaulay VM: Targeting the type 1 insulin-like growth factor receptor as anti-cancer treatment. Anticancer Drugs. 14:669–682. 2003. View Article : Google Scholar : PubMed/NCBI
32	Scartozzi M, Bianconi M, Maccaroni E, Giampieri R, Berardi R and Cascinu S: Dalotuzumab, a recombinant humanized mAb targeted against IGFR1 for the treatment of cancer. Curr Opin Mol Ther. 12:361–371. 2010.PubMed/NCBI
33	Reidy-Lagunes DL, Vakiani E, Segal MF, Hollywood EM, Tang LH, Solit DB, Pietanza MC, Capanu M and Saltz LB: A phase 2 study of the insulin-like growth factor-1 receptor inhibitor MK-0646 in patients with metastatic, well-differentiated neuro-endocrine tumors. Cancer. 118:4795–4800. 2012. View Article : Google Scholar : PubMed/NCBI
34	Pollak M: Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer. 8:915–928. 2008. View Article : Google Scholar : PubMed/NCBI
35	Jameson MJ, Beckler AD, Taniguchi LE, Allak A, Vanwagner LB, Lee NG, Thomsen WC, Hubbard MA and Thomas CY: Activation of the insulin-like growth factor-1 receptor induces resistance to epidermal growth factor receptor antagonism in head and neck squamous carcinoma cells. Mol Cancer Ther. 10:2124–2134. 2011. View Article : Google Scholar : PubMed/NCBI
36	Kavran JM, McCabe JM, Byrne PO, Connacher MK, Wang Z, Ramek A, Sarabipour S, Shan Y, Shaw DE, Hristova K, et al: How IGF-1 activates its receptor. Elife. 3:32014. View Article : Google Scholar
37	Brahmkhatri VP, Prasanna C and Atreya HS: Insulin-like growth factor system in cancer: Novel targeted therapies. BioMed Res Int. 2015:5380192015. View Article : Google Scholar : PubMed/NCBI