MicroRNA-503 acts as a tumor suppressor in glioblastoma for multiple antitumor effects by targeting IGF-1R

Zhang,Yingying; Chen,Xiong; Lian,Haiwei; Liu,Jianmiao; Zhou,Beiyan; Han,Song; Peng,Biwen; Yin,Jun; Liu,Wanhong; He,Xiaohua

doi:10.3892/or.2013.2951

MicroRNA-503 acts as a tumor suppressor in glioblastoma for multiple antitumor effects by targeting IGF-1R

Authors:
- Yingying Zhang
- Xiong Chen
- Haiwei Lian
- Jianmiao Liu
- Beiyan Zhou
- Song Han
- Biwen Peng
- Jun Yin
- Wanhong Liu
- Xiaohua He
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Affiliations: Hubei Province Key Laboratory of Allergy and Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China, Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei 430074, P.R. China, Department of Physiology and Pharmacology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX 77843, USA
Published online on: December 30, 2013 https://doi.org/10.3892/or.2013.2951
Pages: 1445-1452

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Abstract

microRNA (miRNA) dysregulation is associated with various types of human cancer by regulating cancer cell survival, proliferation and invasion. Aberrant expression of microRNA-503 (miR-503) has been reported in several cancer profiles. However, potential linkage of miR-503 levels and the underlying regulatory mechanisms in human glioblastoma multiforme (GBM) remain unclear. In the present study, we showed for the first time that the expression of miR-503 was significantly reduced in GBM tissues and cell lines (U251 and U87MG) relative to normal brain tissues. Furthermore, our results demonstrated that overexpression of miR-503 in GBM cell lines not only suppressed cell proliferation through inducing G0/G1 cell cycle arrest and apoptosis, but also inhibited cancer cell migration and tumor invasion. In addition, we identified insulin-like growth factor-1 (IGF‑1R) receptor mRNA is a bona fide target of miR-503 by computational analysis followed by luciferase reporter assays. Of note, upregulation of miR-503 in GBM cells suppressed endogenous IGF-1R protein expression. Further mechanistic analysis revealed that forced expression of miR-503 inhibited AKT activation, suggesting the tumor suppressive effect of miR-503 in GBM cells is partially mediated by phosphatidylinositol 3-kinase/AKT signaling. Taken together, the results of the present study demonstrated that miR-503 is a tumor suppressor for GBM and a favorable factor against glioma progression through targeting IGF-1R, thus providing a new evidence-supported prognostic marker for GBM diagnosis.

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1	von Deimling A, Louis DN and Wiestler OD: Molecular pathways in the formation of gliomas. Glia. 15:328–338. 1995.PubMed/NCBI
2	Louis DN, Ohgaki H, Wiestler OD, et al: The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol. 114:97–109. 2007. View Article : Google Scholar : PubMed/NCBI
3	Lu J, Getz G, Miska EA, et al: MicroRNA expression profiles classify human cancers. Nature. 435:834–838. 2005. View Article : Google Scholar : PubMed/NCBI
4	Bousquet M, Zhuang G, Meng C, et al: miR-150 blocks MLL-AF9-associated leukemia through oncogene repression. Mol Cancer Res. 11:912–922. 2013. View Article : Google Scholar : PubMed/NCBI
5	Chan JA, Krichevsky AM and Kosik KS: MicroRNA-21 is an antiapoptotic factor in human glioblastoma cells. Cancer Res. 65:6029–6033. 2005. View Article : Google Scholar : PubMed/NCBI
6	Ciafrè SA, Galardi S, Mangiola A, et al: Extensive modulation of a set of microRNAs in primary glioblastoma. Biochem Biophys Res Commun. 334:1351–1358. 2005.PubMed/NCBI
7	Zhang QQ, Xu H, Huang MB, et al: MicroRNA-195 plays a tumor-suppressor role in human glioblastoma cells by targeting signaling pathways involved in cellular proliferation and invasion. Neuro Oncol. 14:278–287. 2012. View Article : Google Scholar : PubMed/NCBI
8	Li X, Ling N, Bai Y, et al: MiR-16-1 plays a role in reducing migration and invasion of glioma cells. Anat Rec. 296:427–432. 2013. View Article : Google Scholar : PubMed/NCBI
9	Lakomy R, Sana J, Hankeova S, et al: MiR-195, miR-196b, miR-181c, miR-21 expression levels and O-6-methylguanine-DNA methyltransferase methylation status are associated with clinical outcome in glioblastoma patients. Cancer Sci. 102:2186–2190. 2011. View Article : Google Scholar : PubMed/NCBI
10	Caporali A and Emanueli C: MicroRNA-503 and the extended microRNA-16 family in angiogenesis. Trends Cardiovasc Med. 21:162–166. 2011. View Article : Google Scholar : PubMed/NCBI
11	Zhao JJ, Yang J, Lin J, et al: Identification of miRNAs associated with tumorigenesis of retinoblastoma by miRNA microarray analysis. Childs Nerv Syst. 25:13–20. 2009. View Article : Google Scholar : PubMed/NCBI
12	Fisher JF and Mobashery S: Mechanism-based profiling of MMPs. Methods Mol Biol. 622:471–487. 2010. View Article : Google Scholar : PubMed/NCBI
13	Hägerstrand D, Lindh MB, Peña C, et al: PI3K/PTEN/Akt pathway status affects the sensitivity of high-grade glioma cell cultures to the insulin-like growth factor-1 receptor inhibitor NVP-AEW541. Neuro Oncol. 12:967–975. 2010.PubMed/NCBI
14	Corbetta S, Vaira V, Guarnieri V, et al: Differential expression of microRNAs in human parathyroid carcinomas compared with normal parathyroid tissue. Endocr Relat Cancer. 17:135–146. 2010. View Article : Google Scholar : PubMed/NCBI
15	Tömböl Z, Szabó PM, Molnár V, et al: Integrative molecular bioinformatics study of human adrenocortical tumors: microRNA, tissue-specific target prediction, and pathway analysis. Endocr Relat Cancer. 16:895–906. 2009.
16	Özata DM, Caramuta S, Velázquez-Fernández D, et al: The role of microRNA deregulation in the pathogenesis of adrenocortical carcinoma. Endocr Relat Cancer. 18:643–655. 2011.PubMed/NCBI
17	Zhou B, Ma R, Si W, et al: MicroRNA-503 targets FGF2 and VEGFA and inhibits tumor angiogenesis and growth. Cancer Lett. 333:159–169. 2013. View Article : Google Scholar : PubMed/NCBI
18	Xiao F, Zhang W, Chen L, et al: MicroRNA-503 inhibits the G1/S transition by downregulating cyclin D3 and E2F3 in hepatocellular carcinoma. J Transl Med. 11:1952013. View Article : Google Scholar : PubMed/NCBI
19	Xu YY, Wu HJ, Ma HD, et al: MicroRNA-503 suppresses proliferation and cell-cycle progression of endometrioid endometrial cancer by negatively regulating cyclin D1. FEBS J. 280:3768–3779. 2013. View Article : Google Scholar : PubMed/NCBI
20	Qiu T, Zhou L, Wang T, et al: miR-503 regulates the resistance of non-small cell lung cancer cells to cisplatin by targeting Bcl-2. Int J Mol Med. 32:593–598. 2013.PubMed/NCBI
21	Finnerty JR, Wang WX, Hébert SS, et al: The miR-15/107 group of microRNA genes: evolutionary biology, cellular functions, and roles in human diseases. J Mol Biol. 402:491–509. 2010. View Article : Google Scholar : PubMed/NCBI
22	Babak T, Zhang W, Morris Q, et al: Probing microRNAs with microarrays: tissue specificity and functional inference. RNA. 10:1813–1819. 2004. View Article : Google Scholar : PubMed/NCBI
23	Baskerville S and Bartel DP: Microarray profiling of microRNAs reveals frequent coexpression with neighboring miRNAs and host genes. RNA. 11:241–247. 2005. View Article : Google Scholar : PubMed/NCBI
24	Peltier HJ and Latham GJ: Normalization of microRNA expression levels in quantitative RT-PCR assays: identification of suitable reference RNA targets in normal and cancerous human solid tissues. RNA. 14:844–852. 2008. View Article : Google Scholar : PubMed/NCBI
25	Furuta M, Kozaki K, Tanimoto K, et al: The tumor-suppressive miR-497-195 cluster targets multiple cell-cycle regulators in hepatocellular carcinoma. PLoS One. 8:e601552013.PubMed/NCBI
26	Caporali A, Meloni M, Völlenkle C, et al: Deregulation of microRNA-503 contributes to diabetes mellitus-induced impairment of endothelial function and reparative angiogenesis after limb ischemia. Circulation. 123:282–291. 2011. View Article : Google Scholar : PubMed/NCBI
27	Sarkar S, Dey BK and Dutta A: MiR-322/424 and -503 are induced during muscle differentiation and promote cell cycle quiescence and differentiation by down-regulation of Cdc25A. Mol Biol Cell. 21:2138–2149. 2010. View Article : Google Scholar : PubMed/NCBI
28	Jiang Q, Feng MG and Mo YY: Systematic validation of predicted microRNAs for cyclin D1. BMC Cancer. 9:1942009. View Article : Google Scholar : PubMed/NCBI
29	Jiang R, Mircean C, Shmulevich I, et al: Pathway alterations during glioma progression revealed by reverse phase protein lysate arrays. Proteomics. 6:2964–2971. 2006. View Article : Google Scholar : PubMed/NCBI
30	Carapancea M, Alexandru O, Fetea AS, et al: Growth factor receptors signaling in glioblastoma cells: therapeutic implications. J Neurooncol. 92:137–147. 2009. View Article : Google Scholar : PubMed/NCBI
31	Friend KE, Khandwala HM, Flyvbjerg A, et al: Growth hormone and insulin-like growth factor-I: effects on the growth of glioma cell lines. Growth Horm IGF Res. 11:84–91. 2001. View Article : Google Scholar : PubMed/NCBI
32	Resnicoff M, Abraham D, Yutanawiboonchai W, et al: The insulin-like growth factor I receptor protects tumor cells from apoptosis in vivo. Cancer Res. 55:2463–2469. 1995.PubMed/NCBI
33	Bellacosa A, Kumar CC, Di Cristofano A and Testa JR: Activation of AKT kinases in cancer: implications for therapeutic targeting. Adv Cancer Res. 94:29–86. 2005. View Article : Google Scholar : PubMed/NCBI
34	Nakada M, Niska JA, Tran NL, et al: EphB2/R-Ras signaling regulates glioma cell adhesion, growth, and invasion. Am J Pathol. 167:565–576. 2005. View Article : Google Scholar : PubMed/NCBI
35	Jones RA, Campbell CI, Petrik JJ and Moorehead RA: Characterization of a novel primary mammary tumor cell line reveals that cyclin D1 is regulated by the type I insulin-like growth factor receptor. Mol Cancer Res. 6:819–828. 2008. View Article : Google Scholar : PubMed/NCBI
36	Wilsbacher JL, Zhang Q, Tucker LA, et al: Insulin-like growth factor-1 receptor and ErbB kinase inhibitor combinations block proliferation and induce apoptosis through cyclin D1 reduction and Bax activation. J Biol Chem. 283:23721–23730. 2008. View Article : Google Scholar
37	Schlenska-Lange A, Knüpfer H, Lange TJ, et al: Cell proliferation and migration in glioblastoma multiforme cell lines are influenced by insulin-like growth factor I in vitro. Anticancer Res. 28:1055–1060. 2008.PubMed/NCBI
38	Oh SH, Kang JH, Kyu Woo J, et al: A multiplicity of anti-invasive effects of farnesyl transferase inhibitor SCH66336 in human head and neck cancer. Int J Cancer. 131:537–547. 2012. View Article : Google Scholar : PubMed/NCBI
39	Saikali Z, Setya H, Singh G and Persad S: Role of IGF-1/IGF-1R in regulation of invasion in DU145 prostate cancer cells. Cancer Cell Int. 8:102008. View Article : Google Scholar : PubMed/NCBI
40	Kang DW and Min do S: Platelet derived growth factor increases phospholipase D1 but not phospholipase D2 expression via NFκB signaling pathway and enhances invasion of breast cancer cells. Cancer Lett. 294:125–133. 2010.PubMed/NCBI
41	Feng X, Aleem E, Lin Y, et al: Multiple antitumor effects of picropodophyllin in colon carcinoma cell lines: Clinical implications. Int J Oncol. 40:1251–1258. 2012.PubMed/NCBI
42	Min S, Liang X, Zhang M, et al: Multiple tumor-associated microRNAs modulate the survival and longevity of dendritic cells by targeting YWHAZ and Bcl2 signaling pathways. J Immunol. 190:2437–2446. 2013. View Article : Google Scholar : PubMed/NCBI