Downregulation of miR-124 promotes the growth and invasiveness of glioblastoma cells involving upregulation of PPP1R13L

Zhao,Wei-Hua; Wu,Sheng-Qi; Zhang,Yang-De

doi:10.3892/ijmm.2013.1365

Downregulation of miR-124 promotes the growth and invasiveness of glioblastoma cells involving upregulation of PPP1R13L

Authors:
- Wei-Hua Zhao
- Sheng-Qi Wu
- Yang-De Zhang
View Affiliations

Affiliations: National Hepatobiliary and Enteric Surgery Research Center, Central South University, Changsha 410008, P.R. China, The Tumor Hospital of Xiangya Medicine School of Central South University, Changsha 410013, P.R. China
Published online on: April 29, 2013 https://doi.org/10.3892/ijmm.2013.1365
Pages: 101-107

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

microRNA-124 (miR-124) plays an important role in regulating growth, invasiveness, stem-like traits, differentiation and apoptosis of glioblastoma cells. PPP1R3L, an inhibitory member of the apoptosis-stimulating protein of p53 family (IASPP), is also able to affect growth, cell cycle progression, metastasis and apoptosis of various types of cancer. To investigate the regulation of PPP1R13L expression by miR-124 and their effects on proliferation, cell cycle transition and invasion in glioblastoma cells, U251 and U373 glioblastoma cells were transfected with miR-124 mimics, its negative control (NC) or an inhibitor. We found that miR-124 was downregulated in glioblastoma tissues, and inversely regulated PPP1R13L expression in U251 and U373 glioblastoma cells. PPP1R13L was found to be a direct target of miR-124 in glioblastoma cells. Overexpression of miR-124 inhibited proliferation, G1/S transition and invasiveness in glioblastoma cells. miR-124 downregulation-mediated malignant progression of glioblastoma was partly attributed to increased PPP1R13L expression. Consequently, our findings provide a molecular basis for the role of miR-124/PPP1R13L in the progression of human glioblastoma and suggest a novel target for the treatment of glioblastoma.

View Figures

View References

1.	Baldi I, Huchet A, Bauchet L and Loiseau H: Epidemiology of glioblastoma. Neurochirurgie. 56:433–440. 2010. View Article : Google Scholar : PubMed/NCBI
2.	Preusser M, de Ribaupierre S, Wöhrer A, et al: Current concepts and management of glioblastoma. Ann Neurol. 70:9–21. 2011. View Article : Google Scholar
3.	Lang MF, Yang S, Zhao C, et al: Genome-wide profiling identified a set of miRNAs that are differentially expressed in glioblastoma stem cells and normal neural stem cells. PLoS One. 7:e362482012. View Article : Google Scholar : PubMed/NCBI
4.	Skalsky RL and Cullen BR: Reduced expression of brain-enriched microRNAs in glioblastomas permits targeted regulation of a cell death gene. PLoS One. 6:e242482011. View Article : Google Scholar : PubMed/NCBI
5.	Sun Y, Zhao X, Zhou Y and Hu Y: miR-124, miR-137 and miR-340 regulate colorectal cancer growth via inhibition of the Warburg effect. Oncol Rep. 28:1346–1352. 2012.PubMed/NCBI
6.	Blenkiron C and Miska EA: miRNAs in cancer: approaches, aetiology, diagnostics and therapy. Hum Mol Genet. 16:R106–R113. 2007. View Article : Google Scholar : PubMed/NCBI
7.	Li Y, Zhao S, Zhen Y, et al: A miR-21 inhibitor enhances apoptosis and reduces G(2)-M accumulation induced by ionizing radiation in human glioblastoma U251 cells. Brain Tumor Pathol. 28:209–214. 2011. View Article : Google Scholar : PubMed/NCBI
8.	Cortez MA, Nicoloso MS, Shimizu M, et al: miR-29b and miR-125a regulate podoplanin and suppress invasion in glioblastoma. Genes Chromosomes Cancer. 49:981–990. 2010. View Article : Google Scholar : PubMed/NCBI
9.	Chen L, Wang X, Wang H, et al: miR-137 is frequently down-regulated in glioblastoma and is a negative regulator of Cox-2. Eur J Cancer. 48:3104–3111. 2012. View Article : Google Scholar : PubMed/NCBI
10.	Wu Z, Sun L, Wang H, et al: MiR-328 expression is decreased in high-grade gliomas and is associated with worse survival in primary glioblastoma. PLoS One. 7:e472702012. View Article : Google Scholar : PubMed/NCBI
11.	Liu Y, Yan W, Zhang W, et al: MiR-218 reverses high invasiveness of glioblastoma cells by targeting the oncogenic transcription factor LEF1. Oncol Rep. 28:1013–1021. 2012.PubMed/NCBI
12.	Li D, Chen P, Li XY, et al: Grade-specific expression profiles of miRNAs/mRNAs and docking study in human grade I–III astrocytomas. OMICS. 15:673–682. 2011.PubMed/NCBI
13.	Li KK, Pang JC, Ching AK, et al: miR-124 is frequently down-regulated in medulloblastoma and is a negative regulator of SLC16A1. Hum Pathol. 40:1234–1243. 2009. View Article : Google Scholar : PubMed/NCBI
14.	Silber J, Lim DA, Petritsch C, et al: miR-124 and miR-137 inhibit proliferation of glioblastoma multiforme cells and induce differentiation of brain tumor stem cells. BMC Med. 6:142008. View Article : Google Scholar : PubMed/NCBI
15.	Pierson J, Hostager B, Fan R and Vibhakar R: Regulation of cyclin-dependent kinase 6 by microRNA 124 in medulloblastoma. J Neurooncol. 90:1–7. 2008. View Article : Google Scholar : PubMed/NCBI
16.	Xie YK, Huo SF, Zhang G, et al: CDA-2 induces cell differentiation through suppressing Twist/SLUG signaling via miR-124 in glioma. J Neurooncol. 110:179–186. 2012. View Article : Google Scholar : PubMed/NCBI
17.	Xia H, Cheung WK, Ng SS, et al: Loss of brain-enriched miR-124 microRNA enhances stem-like traits and invasiveness of glioma cells. J Biol Chem. 287:9962–9971. 2012. View Article : Google Scholar : PubMed/NCBI
18.	Cai Y, Qiu S, Gao X, Gu SZ and Liu ZJ: iASPP inhibits p53-independent apoptosis by inhibiting transcriptional activity of p63/p73 on promoters of proapoptotic genes. Apoptosis. 17:777–783. 2012. View Article : Google Scholar : PubMed/NCBI
19.	Alsafadi S, Tourpin S, André F, Vassal G and Ahomadegbe JC: P53 family: at the crossroads in cancer therapy. Curr Med Chem. 16:4328–4344. 2009. View Article : Google Scholar : PubMed/NCBI
20.	Bergamaschi D, Samuels Y, Sullivan A, et al: iASPP preferentially binds p53 proline-rich region and modulates apoptotic function of codon 72-polymorphic p53. Nat Genet. 38:1133–1141. 2006. View Article : Google Scholar : PubMed/NCBI
21.	Chen J, Xie F, Zhang L and Jiang WG: iASPP is over-expressed in human non-small cell lung cancer and regulates the proliferation of lung cancer cells through a p53 associated pathway. BMC Cancer. 10:6942010. View Article : Google Scholar : PubMed/NCBI
22.	Lu B, Guo H, Zhao J, et al: Increased expression of iASPP, regulated by hepatitis B virus X protein-mediated NF-κB activation, in hepatocellular carcinoma. Gastroenterology. 139:2183–2194. 2010.PubMed/NCBI
23.	Zhang X, Wang M, Zhou C, Chen S and Wang J: The expression of iASPP in acute leukemias. Leuk Res. 29:179–183. 2005. View Article : Google Scholar : PubMed/NCBI
24.	Pang MS, Chen X, Lu B, et al: Lentiviral vector-mediated doxycycline-inducible iASPP gene targeted RNA interference in hepatocellular carcinoma. Chin J Cancer. 29:796–801. 2010. View Article : Google Scholar : PubMed/NCBI
25.	Lin BL, Xie DY, Xie SB, et al: Down-regulation of iASPP in human hepatocellular carcinoma cells inhibits cell proliferation and tumor growth. Neoplasma. 58:205–210. 2011. View Article : Google Scholar : PubMed/NCBI
26.	Liu Z, Zhang X, Huang D, et al: Elevated expression of iASPP in head and neck squamous cell carcinoma and its clinical significance. Med Oncol. 29:3381–3388. 2012. View Article : Google Scholar : PubMed/NCBI
27.	Jiang L, Siu MK, Wong OG, et al: iASPP and chemoresistance in ovarian cancers: effects on paclitaxel-mediated mitotic catastrophe. Clin Cancer Res. 17:6924–6933. 2011. View Article : Google Scholar : PubMed/NCBI
28.	Li G, Wang R, Gao J, Deng K, Wei J and Wei Y: RNA interference-mediated silencing of iASPP induces cell proliferation inhibition and G₀/G₁ cell cycle arrest in U251 human glioblastoma cells. Mol Cell Biochem. 350:193–200. 2011. View Article : Google Scholar : PubMed/NCBI
29.	Arocho A, Chen B, Ladanyi M and Pan Q: Validation of the 2-DeltaDeltaCt calculation as an alternate method of data analysis for quantitative PCR of BCR-ABL P210 transcripts. Diagn Mol Pathol. 15:56–61. 2006.PubMed/NCBI
30.	Aspenström P, Fransson A and Saras J: Rho GTPases have diverse effects on the organization of the actin filament system. Biochem J. 377:327–337. 2004.PubMed/NCBI
31.	Shi XB, Xue L, Ma AH, et al: Tumor suppressive miR-124 targets androgen receptor and inhibits proliferation of prostate cancer cells. Oncogene. Oct 15–2012.(Epub ahead of print). View Article : Google Scholar
32.	Liu T, Li L, Yang W, et al: iASPP is important for bladder cancer cell proliferation. Oncol Res. 19:125–130. 2011. View Article : Google Scholar : PubMed/NCBI
33.	Zhang B, Xiao HJ, Chen J, Tao X and Cai LH: Inhibitory member of the apoptosis-stimulating protein of p53 (ASPP) family promotes growth and tumorigenesis in human p53-deficient prostate cancer cells. Prostate Cancer Prostatic Dis. 14:219–224. 2011. View Article : Google Scholar : PubMed/NCBI
34.	Liu WK, Jiang XY, Ren JK and Zhang ZX: Expression pattern of the ASPP family members in endometrial endometrioid adenocarcinoma. Onkologie. 33:500–503. 2010. View Article : Google Scholar : PubMed/NCBI
35.	Laska MJ, Lowe SW, Zender L, et al: Enforced expression of PPP1R13L increases tumorigenesis and invasion through p53-dependent and p53-independent mechanisms. Mol Carcinog. 48:832–842. 2009. View Article : Google Scholar : PubMed/NCBI