miR-203 sensitizes glioma cells to temozolomide and inhibits glioma cell invasion by targeting E2F3

Tang,Guodong; Wu,Jun; Xiao,Gelei; Huo,Lei

doi:10.3892/mmr.2014.3101

miR-203 sensitizes glioma cells to temozolomide and inhibits glioma cell invasion by targeting E2F3

Authors:
- Guodong Tang
- Jun Wu
- Gelei Xiao
- Lei Huo
View Affiliations

Affiliations: Department of Neurosurgery, Xiangya Hospital, Central South University, Changsha, Hunan 410078, P.R. China
Published online on: December 16, 2014 https://doi.org/10.3892/mmr.2014.3101
Pages: 2838-2844

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Glioma is the most common malignant and fatal primary tumor in the central nervous system in adults. Recent data has suggested a profound role for microRNAs (miRs) in cancer progression. The present study demonstrated, via quantitative polymerase chain reaction (qPCR) analysis, that miR-203 expression was markedly lower in highly invasive U87MG glioma cells and glioma tissues. Wound healing and Transwell assays demonstrated that restoration of miR-203 expression inhibited U87MG cell migration and invasion. Restoration of miR-203 expression additionally sensitized the cells to temozolomide (TMZ) as determined by MTS assay. By contrast, miR-203 inhibition in A172 cells exerted opposite effects. Bioinformatic analysis combined with experimental analysis revealed that miR-203 directly targeted E2F3 via the conserved miR-203 target site within the E2F3 3'-untranslational region. E2F3 knockdown with specific small hairpin RNA also inhibited U87MG cell migration and invasion, and sensitized them to TMZ. Importantly, miR-203 and E2F3 showed inverse expression patterns in invasive glioma tissues, as demonstrated by qPCR and luciferase assay. These results suggested that miR-203 may function as a tumor suppressor in glioma progression and that the miR-203/E2F3 axis may be a novel candidate in the development of rational therapeutic strategies for glioma.

View Figures

View References

1	Wen PY and Kesari S: Malignant gliomas in adults. N Engl J Med. 359:492–507. 2008. View Article : Google Scholar : PubMed/NCBI
2	Hammond SM: MicroRNAs as oncogenes. Curr Opin Genet Dev. 16:4–9. 2006. View Article : Google Scholar
3	Croce CM and Calin GA: miRNAs, cancer and stem cell division. Cell. 122:6–7. 2005. View Article : Google Scholar : PubMed/NCBI
4	Ambros V: MicroRNA pathways in flies and worms: growth, death, fat, stress and timing. Cell. 113:673–676. 2003. View Article : Google Scholar : PubMed/NCBI
5	Brennecke J, Hipfner DR, Stark A, Russell RB and Cohen SM: Bantam encodes a developmentally regulated microRNA that controls cell proliferation and regulates the proapoptotic gene hid in Drosophila. Cell. 113:25–36. 2003. View Article : Google Scholar : PubMed/NCBI
6	Chen CZ, Li L, Lodish HF and Bartel DP: MicroRNAs modulate hematopoietic lineage differentiation. Science. 303:83–86. 2004. View Article : Google Scholar
7	Cheng AM, Byrom MW, Shelton J and Ford LP: Antisense inhibition of human miRNAs and indications for an involvement of miRNA in cell growth and apoptosis. Nucleic Acids Res. 33:1290–1297. 2005. View Article : Google Scholar : PubMed/NCBI
8	Iorio MV and Croce CM: MicroRNAs in cancer: small molecules with a huge impact. J Clin Oncol. 27:5848–5856. 2009. View Article : Google Scholar : PubMed/NCBI
9	Zhang Z, Zhang B, Li W, Fu L, Fu L, Zhu Z and Dong JT: Epigenetic silencing of miR-203 upregulates SNAI2 and contributes to the invasiveness of malignant breast cancer cells. Genes Cancer. 2:782–791. 2011. View Article : Google Scholar
10	Li Y, Yuan Y, Tao K, Wang X, Xiao Q, Huang Z, Zhong L, Cao W, Wen J and Feng W: Inhibition of BCR/ABL protein expression by miR-203 sensitizes for imatinib mesylate. PloS One. 8:e618582013. View Article : Google Scholar : PubMed/NCBI
11	Zhu X, Er K, Mao C, Yan Q, Xu H, Zhang Y, Zhu J, Cui F, Zhao W and Shi H: miR-203 suppresses tumor growth and angiogenesis by targeting VEGFA in cervical cancer. Cell Physiol Biochem. 2:64–73. 2013. View Article : Google Scholar
12	Zhang J, Zhou Y, Wu YJ, Li MJ, Wang RJ, Huang SQ, Gao RR, Ma L, Shi HJ and Zhang J: Hyper-methylated miR-203 dysregulates ABL1 and contributes to the nickel-induced tumorigenesis. Toxicol Lett. 223:42–51. 2013. View Article : Google Scholar : PubMed/NCBI
13	Zhang F, Yang Z, Cao M, Xu Y, Li J, Chen X, Gao Z, Xin J, Zhou S, Zhou Z, et al: MiR-203 suppresses tumor growth and invasion and down-regulates MiR-21 expression through repressing Ran in esophageal cancer. Cancer Lett. 342:121–129. 2014. View Article : Google Scholar
14	van den Heuvel S and Dyson NJ: Conserved functions of the pRB and E2F families. Nat Rev Mol Cell Biol. 9:713–724. 2008. View Article : Google Scholar : PubMed/NCBI
15	Ziebold U, Lee EY, Bronson RT and Lees JA: E2F3 loss has opposing effects on different pRB-deficient tumors, resulting in suppression of pituitary tumors but metastasis of medullary thyroid carcinomas. Mol Cell Biol. 23:6542–6552. 2003. View Article : Google Scholar : PubMed/NCBI
16	Parisi T, Yuan TL, Faust AM, Caron AM, Bronson R and Lees JA: Selective requirements for E2f3 in the development and tumorigenicity of Rb-deficient chimeric tissues. Mol Cell Biol. 27:2283–2293. 2007. View Article : Google Scholar : PubMed/NCBI
17	Chong JL, Wenzel PL, Sáenz-Robles MT, Nair V, Ferrey A, Hagan JP, Gomez YM, Sharma N, Chen HZ, Ouseph M, et al: E2f1–3 switch from activators in progenitor cells to repressors in differentiating cells. Nature. 462:930–934. 2009. View Article : Google Scholar : PubMed/NCBI
18	Veltman JA, Fridlyand J, Pejavar S, Olshen AB, Korkola JE, DeVries S, Carroll P, Kuo WL, Pinkel D, Albertson D, et al: Array-based comparative genomic hybridization for genome-wide screening of DNA copy number in bladder tumors. Cancer Res. 63:2872–2880. 2003.PubMed/NCBI
19	Orlic M, Spencer CE, Wang L and Gallie BL: Expression analysis of 6p22 genomic gain in retinoblastoma. Genes Chromosomes Cancer. 45:72–82. 2006. View Article : Google Scholar
20	Oeggerli M, Tomovska S, Schraml P, Calvano-Forte D, Schafroth S, Simon R, Gasser T, Mihatsch MJ and Sauter G: E2F3 amplification and overexpression is associated with invasive tumor growth and rapid tumor cell proliferation in urinary bladder cancer. Oncogene. 23:5616–5623. 2004. View Article : Google Scholar : PubMed/NCBI
21	Feber A, Clark J, Goodwin G, Dodson AR, Smith PH, Fletcher A, Edwards S, Flohr P, Falconer A, Roe T, et al: Amplification and overexpression of E2F3 in human bladder cancer. Oncogene. 23:1627–1630. 2004. View Article : Google Scholar : PubMed/NCBI
22	Grasemann C, Gratias S, Stephan H, Schüler A, Schramm A, Klein-Hitpass L, Rieder H, Schneider S, Kappes F, Eggert A and Lohmann DR: Gains and overexpression identify DEK and E2F3 as targets of chromosome 6p gains in retinoblastoma. Oncogene. 24:6441–6449. 2005.PubMed/NCBI
23	Andre F, Job B, Dessen P, Tordai A, Michiels S, Liedtke C, Richon C, Yan K, Wang B, Vassal G, et al: Molecular characterization of breast cancer with high-resolution oligonucleotide comparative genomic hybridization array. Clin Cancer Res. 15:441–451. 2009. View Article : Google Scholar : PubMed/NCBI
24	Foster CS, Falconer A, Dodson AR, Norman AR, Dennis N, Fletcher A, Southgate C, Dowe A, Dearnaley D, Jhavar S, et al: Transcription factor E2F3 overexpressed in prostate cancer independently predicts clinical outcome. Oncogene. 23:5871–5879. 2004. View Article : Google Scholar : PubMed/NCBI
25	Borczuk A, Gorenstein L, Walter KL, Assaad AA, Wang L and Powell CA: Non-small-cell lung cancer molecular signatures recapitulate lung developmental pathways. Am J Pathol. 163:1949–1960. 2003. View Article : Google Scholar : PubMed/NCBI
26	Lu KH, Patterson AP, Wang L, Marquez RT, Atkinson EN, Baggerly KA, Ramoth LR, Rosen DG, Liu J, Hellstrom I, et al: Selection of potential markers for epithelial ovarian cancer with gene expression arrays and recursive descent partition analysis. Clin Cancer Res. 10:3291–3300. 2004. View Article : Google Scholar : PubMed/NCBI
27	Feng B, Wang R, Song HZ and Chen LB: MicroRNA-200b reverses chemoresistance of docetaxel-resistant human lung adenocarcinoma cells by targeting E2F3. Cancer. 118:3365–3376. 2012. View Article : Google Scholar